BOROPEPTIDE INHIBITORS OF THROMBIN WHICH CONTAIN A SUBSTITUTED PYRROLIDINE RING

Abstract: This invention relates to the discovery of novel and useful alpha -amino acid analogs, and the pharmaceutically acceptable salts and prodrugs thereof, containing a disubstituted pyrrolidine ring conjugated to an alpha -amino acid, useful as inhibitors of thrombin.

Description: Title Boropeptide Inhibitors of Thrombin which Contain a Substituted Pyrrolidine Ring Field of the Invention This invention relates to the discovery of novel and useful α-amino acid analogs, and the pharmaceutically acceptable salts or prodrugs thereof, as inhibitors of thrombin. These compounds contain a disubstituted- pyrrolidine ring conjugated to an α-amino acid functionalized with an electrophilic group such as boronic acids and their esters, α-perhaloketones and aldehydes. Background of the Invention Thrombin plays several critical roles in hemostasis, the normal physiological process by which bleeding from an injured blood vessel is arrested. Thrombin cleaves soluble fibrinogen to form insoluble fibrin in the. last proteolytic step of both the extrinsic and intrinsic pathways of the coagulation cascade. Fibrin may be further insolubilized through crosslinking by the thrombin-activated enzyme, factor Xllla. In addition, thrombin-induced activation of platelets leads to their aggregation and the secretion of additional factors that further accelerate creation of a hemostatic plug. Thrombin also potentiates its own production by the activation of factors V and VIII. Recent reviews of the roles of thrombin in coagulation have been reported by Fenton in Ann . N. Y. Acad . Scl . 485, 5-15 (1986) ; and Fenton et al . in Blood Coagulati on and Fibrinolysis 2, 69-75 (1991) . Owing to its multiple roles in clot formation, inhibition of thrombin offers a therapeutic opportunity for development of anticoagulants useful in the treatment of thrombosis. Specific thrombin inhibitors are anticipated to exhibit few of the adverse side effects, such as bleeding and interpatient variability, caused by anticoagulants currently in clinical use (B. Furie and B. C. Furie, The New England Journal of Medicine 326, 800-806 (1992)) . A number of naturally occurring thrombin inhibitors have been isolated. These include the marine sponge natural products Theonella sp . nazumamide A, a linear tetrapeptide reported by Fusetani et al . , Tetrahedron Let t . 32, 7073-4 (1991); Theonel la sp . cyclotheonamides A and B reported by Fusenati et al., J. Am . Chem . Soc . 112, 7053-4 (1990) ; and Toxadocia cylindrica toxadocial A, a sulfated C47 aldehyde reported by Nakao et al . , Tetrahedron Let t . 34, 1511-4 (1993) . Hirudin, a 65 amino acid polypeptide, is responsible for the anticoagulant activity of the medicinal leech, Hirudo medi cinalis . Recombinant versions of hirudin disclosed by Brauer et al. in AU-A-45977/85 and compounds incorporating- hirudin fragments that have been disclosed by Maraganore et al . in PCT application WO91/02750; DiMaio et al . , J. Med . Chem . 35, 3331-3341 (1992) ; DiMaio and Konishi, PCT application W091/19734; Witting et al., Biochem . J. 283, 737-743 (1992) ; Krstenansky in European Patent Application EP 372 503 A2; may be clinically useful anticoagulants as suggested by Fareed et al . , Blood Coagulation and Fibrinolysis 2, 135-147 (1991) . Peptide analogs of thrombin substrates and reaction intermediates also inhibit thrombin. Examples of these include the tripeptide aldehyde (D) -Phe-Pro-Arg-H, disclosed by Bajusz et al . , Int . J. Peptide Protein Res . 12, 217-221 (1978) ; a chloromethyl ketone analog (Ac- (D) -Phe-Pro-ArgCH2Cl, disclosed by Kettner and Shaw, Thromb . Res . 14, 969-73 (1979); polyfluorinated analogs such as (D)-Phe-Pro-Arg-CF2~CF3 disclosed by Kolb et al . , AU-B-52881/86; Neises and Ganzhorn, European Patent Application EP 503 203 Al; Neises et al., European Patent Application EP 504 064 Al); and boronic acid analogs (Ac- (D) -Phe-Pro-boroArg, Kettner and Shenvi, European Patent Application EP 0 293 881 A2; Kettner et al., J. Biol . Chem. 265, 18289-97 (1990) . Borolysine, boroornithine and boroarginine inhibitors that contain various amino acid replacements have also been synthesized and shown to inhibit thrombin. Representative examples of these compounds include t-butyloxycarbonyl- (D)-trimethylsilylalanine-Pro- boroArg-pinanediol, disclosed in Metternich, European Patent Application EP 471 651 A2; Ac-(D)-3- napthylalanine-Pro-boroArg pinanediol ester, disclosed in Kakkar et al., PCT Application WO 92/07869; N- ( t- butyloxycarbonyl) - (D)-phenylglycyl- (L)-prolyl- (L)- arginine aldehyde, disclosed in Gesellchen and Shuman, European Patent Application EP 0 479 489 A2 and J. Med . Chem . 36, 314-319 (1993); and (HOOC-CH2) 2" (D -β- cyclohexylalanine-Pro-Arg-CH2-0-CH2-CF3, disclosed by Atrash et al . , European Patent Application EP 530 167 Al. Numerous synthetic thrombin inhibitors, many of which incorporate an arginine or arginine mimic, have also been disclosed. These include arylsulfonylarginine amides such as ( 2R, 4J) -1- [N 2 - (3-ethyl-l, 2, 3, 4- tetrahydro-8-quinolinesulfonyl) -(L)-arginyl]-4-methy1-2- piperidinecarboxylate, disclosed by Okamoto et al . , U.S. Patent No. 4,258,192; Okamoto et al . , Biochem . Biophys . Res . Commun . 101, 440-446 (1981); Kikumoto et al . , Biochemistry 23, 85-90 (1984) ; amidinophenylalanine derivatives such as (2-naphthylsulfonylglycyl) -4- amidino-phenylalanyl piperidine disclosed in Stuber and Dickneite, European Patent Application EP 508 220; amino phenylalanine derivatives, disclosed in Okamoto et al . , U.S. Patent No. 4,895,842; l-[2-[5- (dimethylamino)naphth-1-ylsulfonamido]-3- (2- iminohexahydropyrimidin-5-yl)propanoyl] -4- methylpiperidine dihydrochloride, disclosed in Ishikawa et al., JP 88/227572 and JP 88/227573); and (. )-N- [ (. S) - l-amidino-3-piperidinylmethyl] -a-(o-nitro- benzenesulfonamido) indole-3-propionamide, disclosed in Ackermann et al . , European Patent Application EP 468 231) . Isoquinolinyl guanidino benzoate derivatives, disclosed by Takeshita et al., European Patent Application EP 435 235 Al; and 2-[3-(4- amidinophenyl) Jpropionic acid derivatives, disclosed by Mack et al . , PCT Application WO 93/01208 also act as thrombin inhibitors. Many natural and synthetic thrombin inhibitors contain a 5-membered pyrrolidine ring. In most cases, the pyrrolidine ring is incorporated into the inhibitor as an integral component of the amino acid proline, a 2- substituted pyrrolidine, which in turn is bonded to the remaining atoms of the inhibitor via amide linkages. None of the cited references describe or suggest the new thrombin-inhibiting compounds of the present invention. The novel compounds described in the present invention are substituted at the 4-position of the pyrrolidine ring. Although Winter et al., in European Patent Application WO 91/04247, have disclosed that 4- substituted-(L)-proline can mimic a dipeptide within a larger peptide or protein, and variably substituted prolines have been incorporated into compounds including bradykinin antagonists disclosed by Kyle et al . , J. Med . Chem . 34, 2649-2653 (1991); as well as vasopressin analogs Buku et al . , J. Med . Chem . 30, 1509-1512 (1987), no thrombin inhibitors containing a 5-membered pyrrolidine ring substituted in the manner described here have been disclosed. Despite considerable research in the area, more efficacious and specific thrombin inhibitors are needed as potentially valuable therapeutic agents for the treatment of thrombosis. Summary of the Invention [1] The present invention provides novel compounds of formula (I) : (I) or a pharmaceutically acceptable salt or prodrug thereof, wherein: a) -(C1-C12 alkyl)-X, or b) -(C2-C12 alkenyl) -X, or X is R 3 and R 10 are independently selected at each occurrence from the group consisting of: a) hydrogen, b) halogen,' c) - (CR 6 R 7 ) t W(CR 8 R 9 ) u -R 9 , d) (CR 6 R 7 ) t W(CR 8 R 9 ) u -aryl, e) (CR 6 R 7 ) t W(CR 8 R 9 ) u -heteroaryl, f) (CR 6 R 7 ) t W (CR 8 R 9 ) u -heterocycle, g ) (CR 6 R 7 ) t W(CR 8 R 9 ) u -adamantyl, h) (CR 6 R 7 ) t W(CR 8 R 9 ) u (C 5 -C 7 ) cycloalkyl, i) *0 -7— W — heteroaryl m) o) R fc s) R 3 and R 10 when taken together form a ring such as : a) - (CR 6 R 7 ) t (CR 8 R 9 ) U -W- (CR 8 R 9 ) u (CR 6 R 7 ) t ; b) -(CR 6 R 7 ) t W(CR 8 R 9 ) u -aryl-(CR 8 R 9 ) u W(CR 6 R 7 ) t -; c) - (CR 6 R 7 ) t W(CR 8 R 9 ) u -heteroaryl- (CR 8 R 9 ) U W(CR 6 R 7 ) t -; d) -(CR 6 R 7 ) t W(CR 8 R 9 ) u -heterocycle-(CR 8 R 9 ) u W(CR 6 R 7 ) t -; e) - (CR 6 R 7 ) t (CR 8 R 9 ) u -W- (CR 8 R 9 ) u -w- (CR 6 R 7 ) t -; R 4 and R 5 are independently selected at each occurrence from the group consisting of: a) hydrogen, b) C3 . -C4 alkyl, c) C1-C4 alkoxy, d) C5-C 7 cycloalkyl, e) phenyl, f) benzyl; R 6 , R 7 , R 8 and R 9 are independently selected at each occurrence from the group consisting of: a) hydrogen, b) Ci-Ce alkyl, c) C1-C6 alkoxy, d) C3-C8 cycloalkyl, e) aryl, f) heterocycle, g) heteroaryl, h) -W-aryl, i) -(CH 2 ) w C(=0)OR 4 , j) R 6 or R 7 can alternatively be taken together with R 6 or R 7 on an adjacent carbon atom to form a direct bond, thereby to form a double or triple bond between said carbons, or k) R 8 or R 9 can alternatively be taken together with R 8 or R 9 on an adjacent carbon atom to form a direct bond, thereby to form a double or triple bond between said carbons; R 11 is a) hydrogen, b) C 1 -C 4 alkyl, c) C 1 -C 4 thioalkyl, d) - (CR 6 R ) t W(CR 8 R 9 ) u -aryl, e) - (CR 6 R 7 ) t W(CR 8 R 9 ) u -heteroaryl, f ) - (CR 6 R 7 ) t W(CR 8 R 9 ) u -heterocycle; g) - (CR 6 R 7 ) t W(CR 8 R 9 ) u -R 9 ; R 11 and V, when taken together, can also be: a) keto, b) =NR 10 , c) =C[ (CR 6 R 7 ) t W(CR 8 R 2 ) u R 9 ] 2 ; d) - (CR 6 R 7 ) t W(CR 8 R 9 ) u W-(CR 6 R 7 ) t W(CR 8 R 9 ) u - A is a) -BY 1 ^ 2 , b) -C(=0)CF 3 , c) -C(=0)CF 2 CF 3 , d) -PO3H2 d) -C(=0)H, e) -C (=0) -1-piperdinyl, f) -C(=0)CH 2 OCH 2 CF 3 , g) CH 2 C1 h) SO 2 F; Y 1 and Y 2 are a) -OH, b) -F, C) -NR 4 R 5 -, d) -Ci-Cg alkoxy, or; when taken together Y 1 and Y 2 form: e) a cyclic boron ester where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be N, S, or O, f) a cyclic boron amide where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be N, S, or 0, g) a cyclic boron amide-ester where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be N, S, or 0; W can be independently selected at each occurence from the group consisting of: a) -(CH 2 ) X -, b) -C(=0)-, c) -C(=0)0-, d) -C(=0)NR 4 -, e) -0-, f) -0C(=0)-, g) -0C(=0)0-, h) -0C(=0)NR 4 -, i) -NR 4 -, j) -NR 4 C(=0)-, k) -NR C(=0)0-, 1) -NR 4 C(=0)NR 5 -, m) -NR S(0) p - n) -S(0) p -, o) -S ' (0) p 0-, p) -S(0) D PN 1 R 4 -, q) -S(0) p NR 4 C(=0)-, r) -S(0) p NR 4 C(=0)NR 5 -; V is selected from the group consisting of: a) - (CH 2 ) X -, b) -(CH 2 ) x C(=0)-, c) -(CH 2 ) x C(=0)0-, d) -C(=0) (CH 2 ) X -, e) -0-(CH 2 ) x -, f) -0(CH 2 ) x C(=0)-, g) -0(CH 2 ) x C(=0)0-, h) -0(CH 2 ) x C(=0)NR 4 -, i) -0(CH 2 ) x S(0) p -, j) -(CH 2 ) x S(0) p -, k) -(CH 2 ) x S(0) p 0-, 1) -(CH 2 ) x S(0) p NR 4 -, m) - (CH 2 ) x S(0) p NR 4 C(=0)-, n) - (CH 2 ) x S(0) p NR C(=0)NR 5 -, o) -(CH 2 ) X NR 4 -, p) - (CH 2 ) x NR 4 C(=0)-, q) - (CH 2 ) x NR 4 C(=0)0-, r) - (CK 2 ) x NR 4 C(=0)NR 5 -, S) -(CK 2 ). χ NR 4 S(0) p -; Z is selected from the group consisiting of a) - (CH 2 ) X -, b) -(CH 2 ) x C(=0)-, c) -C(=0) (CH 2 ) X -, d) -(CH 2 ) x C(=0)0-, e) - (CH 2 ) x C(=0)NR 4 -, f) -(CH 2 ) X NR 4 -, g) -(CH 2 ) x NR 4 C(=0)-, h) - (CH 2 ) x NR 4 C(=0)0-, i) -(CH 2 ) χ NR 4 C(=0)NR 5 -, j) -(CH 2 ) x NR 4 S(0) p -, k) -(CH 2 ) x S(0) p -, 1) -(CH 2 ) x S(0) p NR 4 -, m can be 0 to 4; 5 n can be 0 to 4; p can be 0 to 2 0 q can be 0 to 4; r, s, t, u, and v are independently selected at each occurrence from 0 to 6, 5 w and x are independently selected at each occurence from 0 to 4; with the following provisos: C (a) when V is (CH 2 )χ, x cannot be 0 when R 3 is hydrogen; (b) when Z is - (CH 2 ) X C (=0) - and -C (=0) (CH 2 ) X and x is 0, R 1C cannot be halogen. 5 [2] Preferred compounds of formula (I) are those compounds wherein : 0 R 1 is (C3-C 4 alkyl) ; X is selected from the group consisting of: -NHC(=NH)H, -NHC(=NH)NHR 2 , -NH 2 or -SC (=NH) HR 2 ; 5 R 2 is hydrogen or C 1 -C 4 alkyl. [ 3 ] More prefe rred compounds of f ormu la ( I ) are compounds of formula ( Ia ) : ( Ia ) or a pharmaceutically acceptable salts or prodrugs thereof, wherein: R 1 is (C 3 -C 4 alkyl) ; X is selected from the group consisting of: -NHC(=NH)H, -NHC(=NH) NHR 2 , -NH 2 or -SC (=NH)NHR 2 ; R 2 is hydrogen or C 1 -C 4 alkyl; R 3 and R 10 are independently selected at each occ rrence from the group consisting of: a) hydrogen, b) halogen, c) - (CR 6 R 7 ) t W(CR 8 R 9 ) u -R 9 d) - (CR 6 R 7 ) t W(CR 8 R 9 ) u -aryl e) - (CR 6 R 7 ) t W(CR 8 R 9 ) u -heteroaryl; R 4 and R 5 are independently selected at each occurrence from the group consisting of: a) hydrogen, b) C 1 -C 4 alkyl, 1 -. c) C 3. -C4 alkoxy, d) phenyl, e) benzyl; R 6 , R 7 , R 8 , R 9 are independently selected at each occurrence from the group consisting of: a) hydrogen b) Cι-C 6 alkyl, c) aryl, d) -(CH 2 ) w C(=0)OR 4 , or; Y 1 and Y 2 are a) -OH, b) -F, c) -NR R 5 -, d) -Ci-Cβ alkoxy, or; when taken together Y 1 and Y 2 form: e) a cyclic boron ester where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be N, S, or 0, f) a cyclic boron amide where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be N, S, or 0, g) a cyclic boron amide-ester where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be N, S, or 0; W can be independently selected at each occurrence from the group consisting of: b) -O-, c) -S(0) p -, d) -NR 4 -, e) -NR 4 C(=0)-, f ) -NR C ( =0 ) 0- , V is selected from the group consisting of: a) -(CH 2 ) X -, b) -0(CH 2 ) x -, c) -0(CH 2 ) x (C=0)-, d) -(CH 2 ) x S(0) p -, e) -(CH 2 ) X NR 4 - f) -(CH 2 ) χ NR C(=0)-, g) -(CH 2 ) χ NR 4 C(=0)0-; Z is selected from the group consisiting of: a) -(CH 2 ) x C(=0)-, b) -C(=0) (CH 2 ) X -, c) - (CH 2 ) x C(=0)0-, p can be 0 or 2; r can be independently selected at each occurrence from 0 to 3; s can be independently selected at each occurrence from 0 to 3; t can be independently selected at each occurrence from 0 to 2; u can be independently selected at each occurrence from 0 to 2; w can be independently selected at each occurrence from 0 to 2; x can be independently selected at each occurrence from 0 to 3; with the following provisos: (a) when V is (CH 2 ) X , x cannot be 0 when R 3 is hydrogen; (b) when Z is - (CH 2 ) X C (=0) - and -C (=0) (CH 2 ) X and x is 0, R 10 cannot be halogen. [4] Most preferred compounds of formula (I) are those compounds of formula (Ia) (la) or a pharmaceutically acceptable salt or prodrug thereof, wherein: R 1 is (C 3 -C4 alkyl) ; X is from the ' group consisting of -NHC(=NH)K, -NHC (=NH)NHR 2 , -NH 2 or -SC (=NH)NHR 2 ; R 2 is hydrogen or C 1 -C 4 alkyl; R 3 is independently selected from the group consisting of: benzyl, phenyl, phenethyl, (3-phenyl)prop-1-yl, (2- methyl-1-phenyl)prop-2-yl, (2-methy1-2-phenyl)prop- 1-yl, 1, 1-diphenylmethyl, phenoxymethyl, phenylsulfonylmethyl, 2- (τn-fluorophenyl) ethyl, 2- (3-pyridyl) ethyl, (/n-aminophenyl)methyl, (m- methylphenyl) methyl, (p-methylphenyl) methyl, 1- naphthylmethyl; .10 is independently selected from the group consisting of: methyl, t-butoxy, benzyloxy, phenethyl, benzyl, phenoxymethyl, isopropyl, isoamyl, N-methyl -N-t- butoxycarbonylaminomethyl, iV-methylaminomethyl, (m- methyl) phenethyl, (m-fluoro) phenoxymethyl, (m- methyl) phenoxymethyl, (3-pyridyl) ethyl R 11 is hydrogen; Y 1 and Y 2 are a) -OH, b) -F, c) -ΝR R 5 -, d) -Ci-Ce alkoxy, or; when taken together Y 1 and Y 2 form: e) a cyclic boron ester where said chain or ring contains from 2 to 20 carbcn atoms and, optionally, 1-3 heteroatoms which can be N, S, or 0, f) a cyclic boron amide where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be N, S, or 0, g) a cyclic boron amide-ester where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be N, S, or 0; V is independently selected from the group consisting of: 0, -0C(=0)-, S, -NH-; Z is -C(=0)-. ιε [5] Specifically preferred compounds of formula (I) are those compounds of formula (lb) : (lb) selected from the list consisting of: the compound of formula (lb) wherein R 3 is phenyl and R 10 is methyl; the compound of formula (lb) wherein R 3 is phenylmethyl and R 10 is methyl; the compound of formula (lb) wherein R 3 is phenethyl and R 10 is methyl; the compound of formula (lb) wherein R 3 is 3- phenylprop-1-yl and R 10 is methyl; the compound of formula (lb) wherein R 3 is 1,1- dimethyl-2-phenylethyl and R 10 is methyl; the compound of formula (lb) wherein R 3 is 2,2- dimethyl-2-phenylethyl and R 10 is methyl; the compound of formula (lb) wherein R 3 is diphenylmethyl and R 10 is methyl; the compound of formula (lb) wherein R 3 is phenoxymethyl and R 10 is methyl; the compound of formula (lb) wherein R 3 is phenylsulfonylmethyl and R 10 is methyl; the compound of formula (lb) wherein R 3 is {m- fluorophenyl) ethyl and R 10 is methyl; the compound of formula (lb) wherein R 3 is (3- pyridyleτhyl) and R 10 is methyl; the compound of formula (lb) wherein R 3 is phenylethyl and R 10 is phenethyl. [6] Also specifically preferred compounds of formula (I) are those compounds of formula (Ic) : (Ic) selected from the list consisting of: the compound of formula (Ic) wherein V is sulfur, R 3 is phenyl and R 10 is phenmethyl; the compound of formula (Ic) wherein V is oxygen, R 3 is phenylmethyl and R 10 is phenethyl; the compound of formula (Ic) wherein V is oxygen, R 3 is phenylmethyl and R 10 is 3-phenylpropyl; the compound of formula (Ic) wherein V is oxygen, (/n-methyl)phenoxymethyl and R 10 is 3-phenylpropyl; the compound of formula (Ic) wherein V is oxygen, (iD-fluoro)phenoxymethyl and R 10 is 3-phenylpropyl; the compound of formula (Ic) wherein V is oxygen, R 3 is phenylmethyl and R 10 is (m- methylphenyl) ethyl; the compound of formula (Ic) wherein V is oxygen, R 3 is phenylmethyl and R 10 is (m-fluoro)phenethyl; the compound of formula (Ic) wherein V is oxygen, R 3 is phenylmethyl and R 10 is phenoxymethyl; the compound of formula (Ic) wherein V is oxygen, R 3 is (jn-fluorophenyl)methyl and R 10 is phenethyl; the compound of formula (Ic) wherein V is amino, R 3 is phenylmethyl and R 10 is phenethyl; the compound of formula (Ic) wherein V is oxygen, R 3 is phenylmethyl and R 10 is methyl; the compound of formula (Ic) wherein V is oxygen, R 3 is phenylmethyl and R 10 is 2-propyl; the compound of formula (Ic) wherein V is oxygen, R 3 is phenylmethyl and R 10 is isoamyl; the compound of formula (Ic) wherein V is oxygen, R 3 is (.m-methylphenyl)methyl and R 10 is methyl; the compound of formula (Ic) wherein V is oxygen, R 3 is (p-methylphenyl)methyl and R 10 is methyl; the compound of formula (Ic) wherein V is oxygen, R 3 is (1-naphthyl)methyl and R 10 is methyl; the compound of formula (Ic) wherein V is oxygen, R 3 is phenylmethyl and R 10 is N-methyl-JV-t- butoxycarbonylaminomethyl; the compound of formula (Ic) wherein V is oxygen, R 3 is phenylmethyl and R 10 is -V-methylaminomethyl . [7] Also specifically preferred compounds cf formula (I) are those compounds of formula (Id) : selected from the list consisting of: the compound of formula (Id) wherein V is oxygen, R 3 is phenylmethyl and R 10 is phenethyl; the compound of formula (Id) wherein V is oxygen, R 3 is (m-fluorophenyl) ethyl and R 10 is phenethyl. the compound of formula (Id) wherein V is oxygen, R 3 is phenylmethyl and R 10 (m-methyl) phenethyl; Detailed Description of the Invention The "(D)" prefix for the foregoing abbreviations indicates the amino acid is in the (D)-configuration . "D, " indicates the amino acid is present as a mixture of the (D)- and the (L)-configuration. The prefix "bore" indicates amino acid residues where the carboxyl is replaced by a boronic acid or a boronic acid ester. For example, if R 1 is isopropyl and Y- and Y- are OH, the C- terminal residue is abbreviated "boroVal-OH" or "jboroValine" where "-OH" indicates the boronic acid is in the form of the free acid. The pinanediol boronic acid ester and the pinacol boronic acid ester are abbreviated "-C10H16" and "-C6H12", respectively. Examples of other useful diols for esterification with the boronic acids are 1, 2-ethanediol, 1, 3-propanediol, 1, 2-propanediol, 2, 3-butanediol, 1,2- diisopropylethanediol, 5, 6-decanediol, and 1,2- dicyclohexylethanediol . Some common abbreviations used herein are: CBZ or Z, benzyloxycarbonyl; BSA, benzenesulfonic acid; THF, tetrahydrofuran; Boc-, t- butoxycarbonyl-; Ac-, acetyl; pNA, p-nitroaniline; DMAP, 4-dimethylaminopyridine; HOBT, 1-hydroxybenzotriazole and hydrate thereof; DCC, 1, 3-dicyclohexylcarbodimide; Tris, Tris (hydrqxymethyl)aminomethane; MS, mass spectrometry; FAB/MS, fast atom bombardment mass spectrometry. LRMS and HRMS are low and high resolutior. mass spectrometry, respectively, using ammonia (NH 3 -CI) or methane (CH 4 -CI) as an ion source. It is understood that many of the compounds of the present invention contain one or more chiral centers and that these stereoisomers may possess distinct physical and biological properties. The present invention comprises all of the stereoisomers or mixtures thereof. If the pure enantiomers or diasteromers are desired, they may be prepared using starting materials with the appropriate stereochemistry, or may be separated from mixtures of undesired stereoisomers by standard techniques, including chiral chromatography and recrystallization of diastereomeric salts. When any variable (for example, R- through R^-0, m, n, W, Z, etc.) occurs more than one time in any constituent or in formula (I), or any other formula herein, its definition on each occurrence is independent of its definition at every -other occurrence. In the instance that a subscript of a group is 0, it is intended to mean that the previous group is bonded directly with the next group in the sequence. For example, when: R 3 is - (CR 6 R 7 ) t -W- (CR 8 R 9 ) u -aryl, and u is 0 it is the same as : - (CR 6 R ) t -W-aryl . As described broadly above for R 6 and R 7 , in the case "where R 6 (R 8 ) or R' (R 9 ) can alternatively be taken together with R 6 (R 8 ) or R 7 (R 9 ) on an adjacent carbon atom to form a direct bond", this can only occur when t (u) is greater than 1. The structure that would result from: R 3 is -(CR 6 R 7 ) t -W-(CR 8 R 9 ) u -aryl, t = 2, u=2, R 6 and R 7 are taken to for a double bond, and R 8 and R 9 taken to be a triple bond would be: -CR 6 =CR 7 -W-C=C-aryl . The term "amine-blocking group" or "amine- protecting group" as used herein, refers to various acyl, thioacyl, alkyl, sulfonyl, phosphoryl, and phosphinyl groups comprised of 1 to 20 carbon atoms. Substituents on these groups may include either alkyl, aryl and alkaryl which may contain the heteroatoms, 0, S, and N as a substituent or as an inchain component. A number of amine-blocking groups are recognized by those skilled in the art of organic synthesis. Examples of suitable groups include formyl, acetyl, benzoyl, trifluoroacetyl, and methoxysuccinyl; aromatic urethane protecting groups, such as benzyloxycarbonyl; and aliphatic urethane protecting groups, such as t- butoxycarbonyl (also referred to as t-butyloxycarbonyl) or adamantyloxycarbonyl . Gross and Meienhofer, eds . , The Peptides, Vol 3; 3-88 (1981), Academic Press, New York, and Greene and Wuts Protecti ve Groups in Organi c Synthesis, 315-405 (1991), J. Wiley and Sons, Inc., New York describe numerous suitable amine protecting groups and they are incorporated herein by reference for that purpose . "Amino acid residues" as used herein, refers to natural or unnatural amino acid of either (D)- or (L)- configuration. Natural amino acids residues are Ala, Arg, Asn, Asp, Cys, Gin, Glu, Gly, His, lie, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, and Val. Roberts and Vellaccio, The Peptides, Vol 5; 341-449 (1983), Academic Press, New York, describe numerous suitable unnatural amino acids for use in this application and is incorporated herein by reference for that purpose. "Amino acid residue" also refers to various amino acids where sidechain functional groups are coupled with appropriate protecting groups known to those skilled in the art. "The Peptides", Vol 3, 3-88 (1981) describes numerous suitable protecting groups and is incorporated herein by reference for that purpose. As used herein, "alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms; "alkoxy" represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge; "cycloalkyl" is intended to include saturated ring groups, including mono-,bi- and polycyclic ring systems, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl and cyclooctyl, and so forth. "Alkenyl" is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl, propenyl, and the like. "Halo" or "halogen" as used herein refers to fluoro, chloro, bromo, and iodo. The term "aryl" is defined as phenyl, fluorenyl, biphenyl and naphthyl, which may be unsubstituted or include optional substitution with one to three substituents . The term "heteroaryl" is meant to include 5-, 6- or 10-rnernbered mono- or bicyclic aromatic rings which can optionally contain from 1 to 3 heteroatoms selected from the group consisting of 0, N, and S; said ring(s) may be unsubstituted or include optional substitution with one to three substituents. Included in the definition of the group heteroaryl, but not limited to, are the following: 2-, or 5-, or 4-pyridyl; 2-or 3-furyl; 2- or 3-benzofuranyl; 2-, or 3-thiophenyl; 2- or 3- benzo [b]thiophenyl; 2-, or 3-, or 4-quinolinyl; 1-, or 3-, or 4-isoquinolinyl; 2- or 3-pyrrolyl; 1- or 2- or 3- indolyl; 2-, or 4-, or 5-oxazolyl; 2-benzoxazolyl ; 2- or 4- or 5-imidazolyl; 1- or 2- benzimidazolyl; 2- or 4- or 5-thiazolyl; 2-benzothiazolyl; 3- or 4- or 5- isoxazolyl; 3- or 4- or 5-pyrazolyl; 3- or 4- or 5- isothiazolyl; 3- or 4-pyridazinyl; 2- or 4- or 5- pyrimidinyl; 2-pyrazinyl; 2-triazinyl; 3- or 4- 2c cinnolinyl; 1-phthalazinyl; 2- or 4-quinazolinyl; or 2- quinoxalinyl ring. Particularly preferred are 2-, 3-, or 4-pyridyl; 2-, or 3-furyl; 2-, or 3-thiophenyl; 2-, 3-, or 4-quinolinyl; or 1-, 3-, or 4-isoquinolinyl. The term "heterocycle" is meant to include 5-, 6- or 10-membered mono- or bicyclic rings which can optionally contain from 1 to 3 heteroatoms selected from the group consisting of 0, N, and S; said ring(s) may be unsubstituted or include optional substitution with one to three substituents. Included in the definition of the group heterocycle, but not limited to, 2- or 3- pyrrolidinyl, a 2-, 3-, or 4-piperidinyl, or a 1-, 3-, or 4-tetrahdroisoquinolinyl, 1-, 2-, or 4- tetrahydroquinolinyl, 2- or 3-tetrahydrofuranyl, 2- or 3-tetrahydrothiophene, 1-, 2-, 3-, or 4-piperazinyl, and 1-, 2-, 3-, or 4-morpholino. Particularly preferred are 1-, 3-, or 4-tetrahdroisoquinolinyl, 2- or 3- pyrrolidinyl, and 2-, 3- or 4-piperidinyl. The substituents that may be attached to the aryl, heteroaryl or heterocycle ring(s) may be independently selected at each occurrence from the group consisting of: halogen, -CF 3 , C 1 -C 4 alkyl, nitro, phenyl, cyano, - (CH 2 : r R 4 , -(CH 2 ) r C(=0) (CH 2 ) S R 4 , -(CH 2 r C(=0)0(CH 2 ) s R 4 , -<CH 2 r C(=0)N[ (CH 2 ) S R 4 ] [ (CH 2 ) S R 5 ] , methyienedioxy , C1-C4 alkoxy, -CH 2 ) r 0 (CH 2 ) S R 4 , - (CH 2 ) r OC (=0) (CH 2 ) S R 4 , -(CH 2 r OC(=0)0(CH 2 ) s R 4 , -(CH 2 r 0C(=0)N[ (CH 2 ) S R 4 ] [ (CH 2 ) S R5] , -(CH 2 r OC (=0) N [ (CH 2 ) S R 4 ] [C (=0) (CH 2 ) S R 5 ] , -<CH 2 r S(0) p (CH 2 ) s R 4 , - (CH 2 ) r S(0) p (CH 2 ) s C(=0)R 4 , -<CH 2 r S(0) p (CH 2 ) s C(=0)OR 4 , -(CH 2 r S(0) p N[ (CH 2 ) S R 4 ] [ (CH 2 ) S R5], -(CH 2 r S(0) p N[ (CH 2 ) S R 4 J [C(=0) (CH 2 ) S R 5 ] , -(CK 2 r N[ (CH 2 ) S R 4 ] [ (CK 2 ) S R 5 ], / -(CH 2 ) r N[ (CH 2 ) S R 4 ] [C(=0) (CH 2 ) S R 5 ] , -(CH 2 ) r N[ (CH 2 ) S R 4 ] [C(=0)0(CH 2 ) s R 5 ], -(CH 2 ) r N[ (CH 2 ) s R 4 ]CON[ (CH 2 ) S R 4 ] [ (CH 2 ) S R 5 ], -(CH 2 ) r N[ (CH 2 ) s R 4 ]C(=0)-N[ (CH 2 ) S R 4 ] [C (=0) (CH 2 ) S R 5 ] , -(CH 2 ) r N[ (CH 2 ) S R 4 ] [S(0) p (CH 2 ) s R 5 ] . By "stable compound" or "stable structure" is meant herein a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture and formulation into an efficacious therapeutic agent . As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound of formula (I) is modified by making acid or base salts of the compound of formula (I) . Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids and the like . Pharmaceutically acceptable salts of the compounds of the invention can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, methanol, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed. , Mack Publishing Company, Easton, PA, 1985, p. 1418, the disclosure of which is hereby incorporated by reference. "Prodrugs" are considered to be any covalently bonded carriers which release the active parent drug according to formula (I) in vi vo when such prodrug is administered to a mammalian subject . Prodrugs of the compounds of formula (I) are prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds. Prodrugs include compounds of formula (I) wherein hydroxy, amine, or sulfhydryl groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of formula (I) . Synthesis Discussion Compounds of formula (I) can be prepared using the synthetic sequences that follow. The solvents employed are compatible with the reagents selected and the transformations being performed. It will be understood by those skilled in the art of organic synthesis that the order of the transformations proposed will be consistent with functionality present in the molecules and may require judgements during the selection of a procedure for ■ preparation of a compound of the invention . The general synthesis of N-acyl-4- (acyloxy)proline intermediates can be prepared by sequential acylations of the amine and hydroxyl functionalities and is shown in Scheme 1. Scheme 1 (ll) (III) (IV) Thus, as an example, (L) -4-hydroxyproline benzyl ester hydrochloride, which is commercially available, or any other suitably protected hydroxyproline, can be treated with a trialkylamine base, typically 4-methylmorpholine, and an acid chloride (R 10 C C1) to afford acylation product (II) selectively. The hydroxyl group can be converted to a corresponding ester by treatment with a second acid chloride (R 3 COCl) in the presence of a trialkylamine or heterocyclic amine base, such as pyridine, and ' a suitable catalyst, such as but not limited to DMAP to generate (III) . The carboxylic acid of the proline moiety can be liberated by hydrogenation using conditions reported by Hartney and Simonoff, Org . React . VII, 263 (1953) wherein an alcohol solution of the compound (III) may be affected under an atmosphere of hydrogen gas using a suitable catalyst, preferably platinum or palladium on carbon catalyst, to provide (IV) . One may vary the transformations indicated above depending upon the nature of the groups to be appended. One may employ alternative methods such as a mixed anhydride coupling, as reported by Anderson, et al . J. Am. Chem . Soc . 89, 5012 (1967); or the DCC/HOBT protocol described by Konig, and Geiger, Chem . Ber . 103, 788 (1970) to form the requisite amide bond. Also, the DCC/DMAP esterification procedure, reported by Hassner, and Alexanian, Tetrahedron Let t . 19, 4475 (1978) has proved useful for performing the second acylation reaction. Finally, one may choose an ester other than benzyl which might be removed hydrolytically or photilytically, such as photlytic deprotection. For example, with a methyl ester of (II), treatment of an alcoholic solution of the compound with a solution of sodium hydroxide so as to deliver 1 equivalent amount of NaOH followed by acidification should provide the carboxylic acid. The N-acyl-4- (alkoxy)proline intermediates can prepared as shown in Scheme 2. Scheme 2 P= BOC;CBZ The hydroxyl function of an N-protected 4-hydroxyproline (V) can be alkylated according to the method of Smith et al., JV Med . Chem . 31, 875 (1988), by treatment with an alkali metal hydride, such as but not limited to sodium hydride and an alkyl halide (R 3 X) to give (VI) . Removal of the N-protecting group by an appropriate method know to one of skill in the art can provide (VII) : the t- butyl carbamate can be cleaved upon treating with acid under anhydrous conditions; for example, trifluoroacetic acid in dichloromethane solution removes the t-butyl urethane of derivatives of (IV) at ambient temperature as reported by Bryan et . al . , J. Am . Chem . Soc . 99, 2353 (1977); alternatively anhydrous hydrogen chloride in dioxane may be used to prepare the HCI salt. Other methods for protection of the amine are delineated in Greene and Wuts (1991) . The use of benzyl urethane is also viable where hydrogenation over palladium catalyst deliveres the free amine (VII) . Acydlation by one of the methods discussed previously can provide (VIII) . The 4-amino and 4-mercaptoproline intermediates useful for the synthesis of compounds of the formula (I), wherein V is S, NH or derivatives thereof, can be prepared according to Scheme 3. The hydroxyproline ester (IX), wherein the amine is protected as the BOC or CBZ, can be reacted with carbon tetrachloride/ triphenylphosphine according to the method of Webb and Eigenbrot, J. Org . Chem . , 56, 3009 (1991), to provide the chloride- (X) with inversion of stereochemistry. The chloride can be displaced by a sulfur nucleophile, again with inversion of sterochemistry in a manner similar to that reported by Smith et al . (1988) to provide the displacement product (Xllb) , sulfur-containing prolines. Similarly, the chloride can be displaced by sodium azide, which is reduced to the primary amine and converted by reductive amination to provide the displacement products (Xlla), nitrogen-containing prolines. The R 3 group in (XII) used in the displacement reaction need not be the ultimate R 3 of formula (I); methods for their removal are well known to those skilled in the art of organic synthesis . Methods for the attachment cf preferred R 3 are described herein. 5 Δ Scheme 3 These disubstituted prolines (XIIa,b) can be used in an analogous manner to that of (IV) or (VIII) described hereafter. The construction of thrombin inhibitors of the present invention requires the coupling of either of the aforementioned intermediates, (IV), (VIII), or (XII) with a boron-containing fragment followed by manipulation of the pendant functionalities, as shown in Scheme 4. Scheme 4 The synthesis of jborolysine-containing thrombin inhibitors (XVII) begins with the coupling of amine hydrochloride (XIII) , disclosed by Kettner and Shenvi U.S. Patent No. 5.187.147, to provide amide (XIV) . In practice, one may choose from several well-known methods to prepare (XIV) in suitably pure form, as purification of this intermediate is oftentimes impractical. One method calls for the combination of (XIII) and the acid chloride derived from (IV), (VIII) or (XII) in the presence of an amine base, such as but not limited to pyridine. Alternatively, one may employ either the mixed anhydride method, which involves mixing the acid to be coupled with an alkylchloroformate and an tertiary amine base, such as, but not limited to, i-butyl chloroformate and 4-methylmorpholine, followed by addition of the amine discussed previously, to prepare (XIV) from (IV), (VIII) or (XII) ; additionally the DCC/HOBT method may be used to access amines XIV and/or XII Conversion of the bromide to the X group in R 1 of formula (I) can be accomplished by first reaction of bromide (X) with an inorganic azide, such as sodium or potassium azide, in an anhydrous polar aprotic solvent, such as acetone, N,Ν-dimethylformamide or methyl sulfoxide at temperatures ranging from ambient to 130°C; typically reaction with sodium azide in N,JV- dimethylforma ide at 65-70 °C for several hours provides (XV) . Subsequent reduction of the azide function to the amine (XVI) is effected by catalytic hydrogenation of the azide in a solvent, such as an alcohol or ethyl acetate using a suitable transition metal catalyst under an atmosphere of hydrogen gas. Reduction of the azide (XX) in the presence of sulfur-containing prolines (XV, where V is S) can be done according to the method of Knowles et al . , Tetrahedron Lett . , p. 3663 (1978) to provide the amines (XXI) . A variety of alternative methods can be found in the monograph by Hudlicky, Reductions In ' Organi c Synthesis, John Wiley and Sons, pp. 134 (1984) . The amine (XVI) can be isolated as the free base or a salt, typically, but not exclusively hydrochloride or benzenesulfonate; other salts which impart improved physical properties may be preferred. The method described by Matteson et al . , J. Am . Chem . Soc . 102, 7590 (1980) discloses a procedure for removing the pinanediol ester, however, the method employs reagents which may decompose the desired product. The preferred method for preparation of the free boronic acid (XVII) involves transesterification in the presence of excess phenylboric acid. The amidine-type analogs, where the X group in R 1 of formula (I) is modified, can be prepared as shown in Scheme 5. Scheme 5 2 CH (XXV) R=NHC(=NH)H (XXVI) R=NHC(=NH)NH 2 (XXVII) R=NHC(=NH)NHCH The guanidinium analogs can be prepared in a similar manner starting from amine hydrochloride (XVIII) . Amide bond formation using one of the methods previously described provides (XIX) , which can be converted to the azide (XX) by nucleophilic displacement of the bromide. Reduction of the azide using conditions already described can provide the amine (XXI) . Preparation of formamidine (XXII) can be accomplished by reaction of amine (XXI) with ethyl formimidate hydrochloride in the presence of DMAP according to the method of Ohme and Schmitz, Angew, Chem mt . Ed 6,566 (1967) . Elaboration of (XXI) to guanidine (XXIII) can be accomplished by reaction with formamidinesulfonic acid in the presence of DMAP, according to that described in Kim et al., Tetrahedron Let t . 29, 3183 (1988), whereas the analogous N-methylguanidine (XXIV) can be produced when N-methyl- formamidinesulfonic acid is employed according to the method of Walter and Rauden, Liebig Ann. Chem. 722, 98(1969) . As before, transesterification with phenylboric acid yields acids (XXV) - (XXVIII ) . The compounds of formula (I), wherein X is isothiouronium can be prepared as shown in Scheme 6. Scheme 6 (XXVIH) (XXIX) ~ ι Starting from intermediate bromide (XIX) , the ∑ group in formula (I) can be introduced directly by displacement of the halide using thiourea as the nucleophilic species thereby providing boronic ester (XXVIII) . As described 5 previously, transesterification using phenylboric acid yields (XXIX) . Examples 0 Example 78 N 1 - [ (4i?) -N-Acetyl-4- (3-phenylpropionyl) oxy- (L) -prolyl] -R- borolysine, (+) -pinanediol ester Part A: To a solution of ( AR) -4-hydroxy- (L, -proline 5 benzyl ester hydrochloride (2.67 g, 1.04 mol) in dichloromethane (CH 2 C1 2 , 50 mL) at 0 °C was added 4- methylmorpholine (2.50 mL, 2.28 mmol) followed by acetyl chloride (0.72 mL, 1.09 mmol) . The reaction mixture was warmed to room temperature over 12 hours and ethyl 0 acetate (EtOAc, ca . 200 mL) was added. The organic layer was washed with saturated aqueous sodium bicarbonate (NaHC0 3 , 1 30 mL) , water (H 2 0, 1 x 30 mL) , saturated aqueous sodium chloride (NaCl, 1 >: 30 mL) , dried over sodium sulfate (Na 2 S0 4 ) and concentrated 5 under reduced pressure. The resulting oil (1.94 g, l l yield) solidified on standing at room temperature. A sample of (4J ) -N-acetyl-4-hydroxy- ( ) -proline benzyl ester was recrystallized from hexanes :EtOAc to give white plates, mp 99-102 °C (orthorhombic, P2 1 2 1 2 1 , a = C 9.216, b = 9.315, c 15.420 A) . *H NMR (300 MHz, CDC1 3 ) δ 7.35 (comp, 5H) , 5.17 (s, 2H) , 4.63 (m, 1H) , 3.79 (dd, J= 10.6,4.6 Hz, 1H), 3.50 (d, J= 10.6 Hz, 1H) , 2.29 (d, J= 4.4 Hz, 1H), 2.24 (m, 1H) , 2.11 (m, 1H) , 2.09 (s, 3H) ; LRMS 264 (M+H, base), 281 (M+NH 4 ); Anal. Calcd for 5 C 14 H 17 N0 4 : C, 63.87; H, 6.51; N, 5.32. Found: C, 63.84; K, 6.41; N, 5.38. Part B: To a solution of the product from Part A (370 mg, 1.41 mmol) and pyridine (0.17 mL, 2.10 mmol) in CH 2 C1 2 (14 mL) at 0 °C was added 3-phenylpropionyl 5 chloride (0.23 mL, 1.55 mmol) . The reaction mixture was warmed to room temperature over 3 hours and added to EtOAc (ca. 75 mL) . The organic layer was washed with sat. aq. NaHC0 3 (1 x 25 mL) , half-saturated aqueous copper (II) sulfate (1 x 25 mL) , sat. aq. NaCl (1 x 25 0 mL) , dried (Na 2 S0 4 ) and was concentrated under reduced pressure. The residue was purified by flash chromatography, elution with 2:1 EtOAc-hexanes to give (4.R) -N-acetyl-4- (3-phenylpropionyl) oxy- (L)-proline benzyl ester (340 mg) as an oil in 61% yield. 1 H NMR (300 MHz, 5 CDC1 3 ) δ 7.37 (comp, 5H) , 7.28 (m, 2H) , 7.19 (m, 3H) , 5.30 (m, IH) , 5.18 ( , 2H) , 4.51 (dd, J= 8.4, 8.0 Hz, IH) , 3.84 (dd, J= 11.7, 4.7 Hz, IH), 3.46 (d, J= 11.7 Hz, IH) , 2.93 (t, J= 7.5 Hz, 2H) , 2.64 (t, J= 7.5 Hz, 2H) 2.28 (m, IH) , 2.13 (m, IH) , 2.03 (s, 3H) ; LRMS 396 0 (M+H, base) . Part C: A solution of the product from Part E (340 mg, 0.86 mmol) together with palladium on charcoal (50 mg) in methanol (MeOH, 9 mL) was stirred under hydrogen (1 5 at ) for 2 hours. The reaction mixture was filtered through a pad of Celite with additional MeOH (ca. 10 mL) and the filtrate was concentrated under reduced pressure to give (4.R) -N-acetyl-4- (3-phenylpropionyl) oxy- (L)- proline (245 mg) as a foam in 93% yield. 1 H NMR (300 C MHz, CDCI 3 ) δ 7.27 (comp, 5H) , 5.28 (m, IH) , 4.57 (t, J= 7.7 Hz, IH), 4.38 (br s, IH), 3.76 (dd, J= 11.9, 4.5 Hz, IH), 3.49 (s, IH), 2.95 (t, J= 7.3 Hz, 2H) , 2.66 (t, J= 7.3 Hz, 2H), 2.56 (m, IH) , 2.26 (m, IH) , 2.07 (s, 3H) ; LRMS 306 (M+H), 173 (base) . Part D: To a solution of the product from Part C (240 mg, 0.79 mmol) and 4-methylmorpholine (0.26 mL, 2.36 mmol) in tetrahydrofuran (THF, 6 mL) at -20 °C was added i-butyl chloroformate (0.11 mL, 0.87 mmol) after which the reaction mixture was stirred for 2 minutes. A solution of (1R) -5-bromoaminopentane-l-boronic acid (+)- pinanediol ester (299 mg, 0.79 mmol) in N, N- dimethylformamide (DMF, 2 mL) was added, the reaction was stirred at -20 °C for 15 minutes and warmed to room temperature over 18 hours. The reaction mixture was poured into EtOAc (ca. 50 mL) and washed with H 2 0 (3 x 15 mL) , and sat. aq. NaCl (1 x 15 mL) dried (Na 2 S0 4 ) and concentrated under reduced pressure to give (l.R)-5- bromo- [ (4.R) -N-acetyl-4- (3-phenylpropionyl) oxy- (u- prolyl]aminopentane-1-boronic acid, (-<-) -pinanediol ester (475 mg) as an oil in 96=s yield. LRMS 631,633 (M+H), 551 (base) . Part E: A mixture of the product from Part D (470 mg, 0.75 mmol) and sodium azide (Na 3 , 97 mg, 1.50 mmol) in DMF (8 mL) was heated at 65-70 °C for 4 hours. The mixture was poured into EtOAc (ca. 75 mL) . and washed with H 2 0 (3 x -20 mL) , sat. aq. NaCl (1 x 20 mL) , dried (Na 2 S0 4 ), and concentration under reduced pressure to give (1J ) -5-azido- [ ( R) -N-acetyl-4- (3- phenylpropionyl) oxy- (L)-prolyl] aminopentane-1-boronic acid, (+) -pinanediol ester. (403 mg) as an oil in 91 c : yield. LRMS 594 (M+H, base) . Part F: A solution of the product from Part E (388 mg, 0.65 mmol) in MeOH (7 mL) together with palladium hydroxide on charcoal (35 mg) was stirred under hydrogen (1 atm) for 3 hours. The reaction mixture was filtered through a pad of Celite with additional MeOH (ca. 10 mL) and the filtrate was concentrated under reduced pressure to give 320 mg of the title compound as a foam in 86'ε yield. LRMS 568 (M + 1, base); HRMS Cacld for C 31 H 47 BN 3 0 6 : 568.3558. Found: 568.3558. Example 154 N 1 - [ ( 4R) -N- (3-Phenylpropionyl) -4- (benzyl) oxy- (L)-prolyl]- Λ-borolysine, benzenesulfonate To a mixture of Example 303 (1.95 g, 2.52 mmol) in H 2 0 (10 mL) , Et 2 0 (15 mL) , and sufficient MeOH (ca. 1.5 mL) to maintain a clear, biphasic system was added phenylboric acid (1.54 g, 12.6 mmol) . The mixture was stirred for 14 hours, the layers were separated and the aqueous phase was extracted with Et 0 (5 x 20 mL) . The aqueous layer was concentrated under reduced pressure to give the title compound (1.20 g) as an amorphous powder in 75% yield. LRMS 482 (M+H), 464 (base); HRMS Calcd for C 28 H 39 BN 3 0 5 (ethylene gycol ester) : 508.2983. Found: 508.2999. Example 302 N 1 - [ ( .R) -N- (3-Phenylρropionyl) -4- (phenyl)thio- (L)- prolyl] -.R-borolysine (->-) -pinanediol ester, hydrochloride Part A: The commercially available starting material, (4.R) -N-BOC-4-hydroxy- (L)-proline methyl ester was dissolved in CH C1 2 (140 mL) and carbon tetrachloride (140 mL) and triphenylphosphine (42.56 g, 162.2 mmol) was added. The mixture was allowed to stir for 2 hours, ethanol (15 mL) was added and stirring was continued for an additional 16 hours. The mixture was concentrated under reduced pressure to 100 mL, cooled to -20 °C and Et 2 0 (200 mL) was added. The resulting precipitate was suction filtered ' and washed with Et 0. The solid was further purified by flash chromatography, elution with 1:1 Et 2 0-hexanes gave (4S) -N-BOC-4-chloro- (L) -proline methyl ester (17.03 g) as an oil in 84% yield. l H NMR (300 MHz, CDC1 3 ) δ 4.37 (m, 2H) , 3.95 (m, IH) , 3.75 (s, 3H), 3.63 (m, IH) , 2.63 (m, IH) , 2.38 (m, IH) , 1.45 (s, 9H) . Part B: A solution of the product from Part A (17.03 g, 64.5 mmol) in trifluoroacetic acid (20 mL) and CH 2 C1 2 (20 mL) was stirred 18 hours. The reaction mixture was concentrated under reduced pressure to give (4S)-4- chloro-(L)-proline methyl ester (18.05 g) as an oil in quanitative yield. -H NMR (300 MHz, CDCI 3 ) δ 4.75 (comp, 2H), 3.87 (comp, 2H) , 3.94 (s, 3H), 2.99 ( , IH) , 2.77 (m, IH) . Part C: A solution of the product from Part B (30.28 g, 109 mmol) in CH 2 C1 2 (50 mL) was cooled to 0 °C and E 3 N (45.6 mL, 327 mmol) followed by hydrocinnamoyl chloride (17.8 mL, 120 mmol) were added slowly in order to maintain an internal temperature less than 10 °C . After stirring six hours, H 0 (50 mL) was added to the reaction mixture. The resulting solution was extracted with CH 2 C1 2 (3 x 50 mL) . The organics were washed with H 0 (25 mL) , dried with MgS0 4 and concentrated under reduced pressure to give (4S) -N- (3-phenylpropionyl) -4- c loro- (L)-proline methyl ester (17.44 g) as a waxy solid in 54% yield. LRMS 296.1 (base, M+H) . Part D: EtOH (50 mL) was cooled to 0 °C and sodium (0.78 g, 33.8 mmol) was added. After the hydrogen evolution ceased, thiophenol (3.72 g, 33.8 mmol) was added and the reaction mixture stirred for 15 minutes at 0 °C, and the product from Part C (5 g, 16.9 mmol) was added. The stirring was continued for an additional 16 hours at room temperature. The mixture was concentrated under reduced pressure, diluted with water (20 mL) and acidified with IN HCI to pH . The aqueous solution was extracted with EtOAc (3 x 30 mL) , the organics dried with Na 2 S0 4 and concentrated under reduced pressure. The residue was further purified by flash chromatography, elution with chromatographed with 1:3 5 EtOAc-hexanes gave 2.06 g of ( 4R) -N- (3-phenylpropionyl) - 4- (phenyl) thio-(L)-proline in 25% yield. LRMS 356.1 (M+H, base) . Part E: Using the method described above for the preparation of Example 78, Part D, ( 1R) -5-bromo- [ (4R) -N- 0 (3-phenylpropionyl)-4- (phenyl)thio- (L)- prolyl]aminopentane-l-boronic acid, (+) -pinanediol ester was isolated (2.43 g) as an oil in 85% yield. LRMS 681.2 683.2 (M+H, base) . Part F: Using the method described above for Example 5 78, Part E, the intermediate ( 1R) -5-azido- [ (4.R) -N- (3- phenylpropionyl) -4- (phenyl) thio- ( )-prolyl] aminopentane- 1-boronic acid, (+) -pinanediol ester was isolated (2.42 g) as an oil in quantitative yield. Part G: A solution of the product from Part F (2.42 g, C 3.76 mmol) in 1, 3-propanedithiol (1.62 g, 15 mmol), triethylamine (1.52 g, 15 mmol) and methanol (20 mL) was stirred at 50 °C for 24 hours. The reaction mixture was concentrated under reduce pressure and purified by flash chromatography through florosil, eluting with 1:9 5 MeOH-CH Cl 2 . The concentrated residue was dissolved in diethyl ether (10 mL) , acidified with 1 equivalent of IN HCI in Et 2 0 and concentrated to give the title compound (0.73 g) as a solid in 31% yield. LRMS 617.3 (M+H, base) . HRMS Cacld for C 35 H 48 BN 3 θ 4 S: 617.34583. Found: 0 617.34580. Example 303 N 2 - { (4.R)-N- (3-Phenylpropionyl)-4- (benzyl)oxy- (L)-prolyl]- .R-borolysine, (+)-pinanediol ester Part A: A solution of the commercially available starting material, (4.R) -N-BOC-4- (benzyl) oxy- ( )-proline, previously reported by Smith et al., J. Med . Chem . 31, 875 (1988); (2.11 g, 6.57 mmol), in CH 2 C1 2 (27 mL) was treated with anhydrous hydrogen chloride in dioxanes (4 M, 6.60 mL) . The reaction mixture was stirred for 18 hours, during which time a white precipitate formed. The reaction was diluted with diethyl ether (Et 2 0, ca . 100 mL) and the solid material was collected by suction filtration to afford (4.R) -4- (benzyl) oxy- (L)-proline hydrochloride (1.60 g) as a white powder in 95% yield. -H NMR (300 MHz, DMSO-d 6 ) δ 10.2 (br s, IH), 7.36 (comp, 5H) , 4.52 (s, 2H) , 4.37 (dd, J= 10.8,7.5 Hz, IH) , 4.31 (m, IH) , 3.43 (dd, J= 12.5,4.4 Hz, IH) , 3.33 (d, J= 12.5 Hz, IH), 2.48 (m, IH) , 2.11 (m, IH) ; LRMS 222 (M+H, base) . Part B: A suspension of the product from Part A (1.5C g, 5.83 mmol) in CH 2 C1 2 (58 mL) at 0 °C was treated with 3-phenylpropiόnyl chloride (0.95 mL, 6.41 mmol) followed by 4-methylmorpholine (1.92 mL, 17.5 mmol) . The reaction mixture was warmed to room temperature over 20 hours, treated with 2M aqueous hydrochloric acid (HCI) until pH = 2, and added to EtOAc (ca. 200 mL) . The organic layer was washed with H 2 0 (3 x 50 mL) , sat. aq. NaCl (1 x 50 mL) , dried (MgS0 ) and concentrated under reduced pressure. The resulting solid was recrystallized from hexanes-EtOAc and gave a first crop (1.33 g, mp 127-129 °C) and a second crop (0.37 g, mp 122-125 °C) of (4i)-N- (3-phenylpropionyl) -4- (benzyl) oxy- (D-proline as colorless plates in a total of 82% yield, (monoclinic, P2 l r a = 6.196, b = 9.101, c = 16.477A, β = 98.98 °) 2 H NMR (300 MHz, CDC1 3 ) δ 7.29 (comp, 10H), 4.95 (br s, IH) , 4.69 (dd, J= 8.1, 6.2 Hz, IH) , 4.50 (ABq, ΔCXAB = 32.5 Hz, J AB = 11.7 Hz, 2H) , 4.20 (quin, J= 4.8 Hz, IH), 3.46 (d, J= 4.8 Hz, 2H) , 2.98 (t, J= 7.7 Hz, 2H) , 2.59 (t, J= 7.4 Hz, 2H) , 2.50 (m, IH) , 2.23 (ddd, J= 13.5, 8.4, 5.0 Hz, IH) ; LRMS 354 (M+H, base) ; Anal. Calcd for C 21 H 23 N0 4 : %C, 71.37; %H, 6.56; %N, 3.96. Found: %C, 71.39; %H, 6.57; %N, 3.92. Part C: Using the method described above for the preparation of Example 78, Part D, (1R) -5-bromo- [ ( R) -N- (3-phenylpropionyl) -4- (benzyl) oxy- (L)- prolyl]aminopentane-1-boronic acid (+) -pinanediol ester was isolated (2.80 g) as an oil in 90% yield. LRMS 679, 681 (M+H, base) . Part D: Using the method described above for Example 78, Part E, (1R) -5-azido- [ (4. ) -N- (3-phenylpropionyl) -4- (benzyl) oxy- ( )-prolyl]aminoρentane-1-boronic acid (+)- pinanediol ester was isolated (2.31 g) as an oil in 94% yield. LRMS 642 (M+H, base) . Part E: A solution of product from Part D (2.24 g, 3.50 mmol) in ' MeOH (35 mL) together with palladium on charcoal (225 mg) was stirred under hydrogen (1 atm) for 1 hour. The reaction mixture was filtered through a pad of Celite with additional MeOH (ca. 30 mL) and the filtrate was concentrated under reduced pressure to give a foam which contained a small amount of unreacted azide. This material was resubjected to the hydrogenation conditions described above to afford the title compound (2.00 g) as a white foam in 93% yield. LRMS 616 (M+H, base) . Example 303a N 1 - [ (4R)-N- (3-Phenylpropionyl) -4- (benzyl) oxy- (U -prolyl] - Λ-borolysine, (+) -pinanediol ester, benzenesulfonate A solution of Example 303 (2.00 g, 3.25 mmol) in methanol (25 mL) was treated with a solution of benzenesulfonic acid (0.514 g, 3.25 mmol) in methanol (8 mL) . The mixture was allowed to stand at room temperature for 15 minutes and concentrated under reduced pressure to give a foam. The residue was washed with Et 2 0 (2 x 25 mL) , which was decanted, then dissolved in EtOAc (ca. 20 mL) and triturated with Et 2 0 (ca. 75 mL) to afford an oily material which was washed with Et 0 (2 x 25 mL) . The excess solvent was removed in vacuo to give the title compound (2.00 g) as a powder in 79% yield. LRMS 616 (M+H, base); HRMS Calcd for C 36 H 51 BN 3 0 5 : 616.3922. Found: 616.3921. E ample 375 N J - [ ( 4R) -N- (3-Phenylpropionyl) -4- (benzyl) amino- (L)- prolyl]-J-borolysine, (+) -pinanediol ester, hydrochloride Part A: A mixture of the product from Example 302, Part C (3.00g, 10.1 mmol) and NaN 3 (3.30 g, 5C.7 mmol) in DMF (15 mL) was heated to 75 °C for 18 hours. Tne reaction mixture was dissolved in H 2 0 (25 mL) . The aqueous solution was extracted with Et 2 0 (3 x 25 mL) , dried with MgS0 4 and concentrated to give (4Λ)-N-(3- phenylpropionyl) -4-azido- (L)-proline methyl ester (2.13 g) as an oil in 83% yield. -H NMR (300 MHz, CDC1 3 ) δ 7.25 (comp, 5H) , 4.56 ( , IH) , 4.26 (m, IH) , 3.77 (s, 3H) , 3.75 (m, IH) , 3.40 (dd, J = 8, 2 Hz, IH) , 2.97 ( , 2H) , 2,60 (m, 2H) , 2.32 (comp, 2H) . LRMS 303.1 (M+H, base) . Part B: Using the method described above for the preparation of Example 78, Part F, ( 4Λ) -N- ( 3- phenylpropionyl) -4-amino-(L)-proline methyl ester was isolated (2.43 g) as an oil in 85% yield. --R ΝMR (300 5 MHz, CDCI3) δ 7.24 (comp, 5H) , 4.58 (m, IH) , 3.74 (m, 2H) , 3.73 (s, 3H) , 3.01 (m, 3H) , 2.60 (m, 2H) , 2.12 (m, IH) , 1.94 (m, IH) . LRMS 277.1 (M+H, base) . Part C: A_mixture of the product from Part B (1.51 g, 5.46 mmol), benzaldehyde (0.58 g, 5.46 mmol), potassium 0 acetate (0.54 g, 5.46 mmol) and 5% palladium on charcoal (0.21 g) was stirred in MeOH (25 mL) under hydrogen (3 atm) for 5 hours. The reaction mixture was filtered through a pad of Celite with additional MeOH (ca. 10 mL) and the filtrate concentrated under reduced pressure to 5 give (4.R) -Ν- (3-phenylpropionyl) -4- (benzyl) amino- (L)- proline methyl ester (2.00 g) as an oil in quantitative yield. 1 H ΝMR (300 MHz, CDCI3) δ 7.27 (comp, 10H) , 4.58 (m, IH) , 3.73 (comp, 4H) , 3.50 (m, IH) , 3.44 (s, 3H) , 3.15 (m, IH), 2.96 (t, J = 7 Hz, 2H) , 2.55 (m, 2H) , 2.09 C (m, 2H) . LRMS 367.2 (M+H, base) . Part D: A solution of the product from Part C (2.00 g, 5.46 mmol) methanol (15 mL) and IN sodium hydroxide (9 mL) was stirred for 24 hours. The pH of the solution was adjusted to 6 with IN HCI and a white precipitate 5 formed. The solid material was collected by suction filtration to give (4R) -Ν- (3-phenylpropionyl) -4- (benzyl) amino-( )-proline (1.31 g) as a white powder in 68% yield. LRMS 353.2 (M+H, base) . Part E: Using the method described above for the 0 preparation of Example 78, Part D, ( 1R) -5-bromo- [ (4J ) -Ν- (3-phenylpropionyl) -4- (benzyl) amino- (L)- prolyl]aminopen v tane-l-boronic acid, (+) -pinanediol ester was isolated (0.71 g) as an oil in 49% yield. LRMS 678.3 680.3 (M+H, base) . Part F: Using the method described above for Example 78, Part E, the intermediate (li?) -5-azido- [ (4i?) -N- (3- phenylpropionyl) -4- (benzyl) amino- (L)-prolyl] aminopentane- 1-boronic acid, (+)-pinanediol ester was isolated (0.45 g) as an oil in 67% yield. Part G: A solution of the product from Part F (0.45 g, 0.70 mmol) in MeOH (5 mL) together with 20% palladium hydroxide on charcoal (0.04 g) was stirred under hydrogen (1 atm) for 4 hours. The reaction mixture was filtered through a pad of Celite with EtOAc (ca. 10 L) . The filtrate was concentrated under reduced pressure and purified by flash chromatography through florosil, eluting with 1:9 MeOH-CH 2 Cl 2 . The concentrated residue was dissolved in Et 0 (10 mL) , acidified with 2 equivalents of IN HCI in Et 0 and concentrated to give the title compound (0.27 g) as a oil in 56% yield. LRMS 615. (M+H, base) . Example 1641 N 1 - [ (4i?) -N- (Benzyloxy) carbonyl-4- (benzyl) oxy- (D-prolyl ] i-borothioarginine, (+) -pinanediol ester Part A: Using the method described above for Example 78, (li?) -4-bromo- [ (4i?) -N- (benzyloxy) carbonyl-4- (benzyl) oxy- (L)-prolyl]aminobutane-1-boronic acid, (+)- pinanediol ester (370 mg) was prepared as an oil in 99% yield. LRMS 667, 669 (M+H), 587 (base) . Part B: A mixture of the product from Part A (365 mg, 0.55 mmol) and thiourea (83 mg, 1.10 mmol) in ethanol (EtOH, 10 mL) was heated at reflux for 16 hours and cooled to room temperature. The reaction was poured into Et 2 0 (ca. 120 mL) and concentrated under reduced 46 pressure. The residue was triturated with Et 2 0 (ca. 50 mL) , which was decanted. Purification of the residue by size exclusion chromatography on Sephadex LH-20, elution with MeOH, gave a glass which was dissolved in THF (1.5 mL) and treated with Et 2 0 (ca. 20 mL) to give a solid. The solid was washed with Et 2 0 (ca. 10 mL) and dried to afford the title compound (125 mg) as a white solid in 31% yield, mp 79-82 °C. LRMS 663 (M+H, base) ; HRMS Calcd for C 35 H 48 BN 4 0 6 S : 663.3388. Found: 663.3374. Based on the representative examples detailed above, the following compounds of the invention can be prepared, as shown in Tables 1-20 Tab l e 1 Ex. No RA R 6 R 7 R8 R9 R 10 W t u Data 1 H CH 3 CO 0 0 2 H CH 3 CH 2 CO 0 0 3 H H H CH3 CH 2 CO 1 0 4 H H H H H CH3 CH 2 CO 1 1 5 H CH3 CH3 CH3 CH 2 CO 1 0 6 H CH3 CH3 CH 3 CH 2 CO 0 1 7 H Ph H CH 3 CO 0 ] 8 H H H CH 3 O CO 0 9 H CH 3 CH 3 CH3 O CO 0 10 H H H CH 3 S0 2 CO 0 1 1 2-CH 3 H H CH 3 CH 2 CO 0 12 3-CH3 H H CH 3 CH 2 CO 0 13 2, 3-diCH 3 H H CH 3 CH 2 CO 0 14 2-F H H CH 3 CH 2 CO 0 15 3-F H H CH 3 CH 2 CO 0 16 4-F H H CH3 CH 2 CO 0 17 2-NH 2 H H CH 3 CH 2 CO 0 18 3-NH 2 H H CH 3 CH 2 CO 0 19 2-N0 2 H H CH 3 CH 2 CO 0 20 3-N0 2 H> H CH 3 CH 2 CO 0 21 2-N H H CH 3 CHo CO 0 Table 2 Ex.No RA R6 R7 R8 R 9 R l0 W t u Data 76 H CH 3 CO 0 0 A 77 H CH 3 CH 2 CO 0 0 B 78 H H H CH 3 CH 2 CO 1 0 c 79 H H H H H CH 3 CH 2 CO 1 1 D 80 H CH3 CH 3 CH 3 CH 2 CO 1 0 E 81 H CH 3 CH 3 CH 3 CH 2 CO 0 1 F 82 H Ph H CH 3 CO 0 1 G 83 H H H CH 3 O CO 0 H 84 H CH 3 CH 3 CH 3 o CO 0 85 H H H CH 3 so 2 CO 0 86 2-CH 3 H H CH 3 CH 2 CO 0 87 3-CH3 H H CH 3 CH 2 CO 0 88 2, 3-diCH 3 H H CH 3 CH 2 CO 0 89 2-F H H CH 3 CH 2 CO 0 90 3-F H H CH 3 CH 2 CO 0 91 4-F H H CH 3 CH 2 CO 0 92 2-NH2 H H CH 3 CH 2 CO 0 93 3-NH 2 H H CH 3 CH 2 CO 0 94 2-N0 2 H H CH 3 CH 2 CO 0 95 3-N0 2 H ' H CH 3 CH 2 CO 0 96 2-N H H CH 3 CH 2 CO 0 X X X X X X X X X X X I LOX X X X X X X X X X X X X X I LOx x x LxO x x x X X X X X X X X X X X I LX.J X X X X X X X X X X X X X X I LxO x LxO x x x I I I I I I I I I I I o X I I I I I I I I I I I I I I I oX I I I I I I I LO LO I I I I I I I I I I I X I I I I I I I I I I I I I I I I I I I I I I L LO o o o o o o o o o o o o o o o o o tO SJ SJ tO SJ SJ SJ tO tO SJ TJ TJ TJ TJ TJ TJ TJ TJ TJ TJ • - ^ ^ ^ <£. ^ <£, r-r rr rr rr rr rr rr rr rr rr to to SJ SJ NJ NJ NJ TJ TJ TJ TJ TJ TJ TJ rr tr tr tr tr tr tr O O O O O O O O O O o o o o Λ Λ _ 6666 6 6 6 666 ^ ~ ri ° ° o o o o o o o o o o o o o o o o o o o o ' δ o o ' δ ^ ' δ ' δ ' δ -9 o 9 o 9r> o 9 o o n o o o o o o o o o o o o o o o o o o o o O O C O O O O O O O ^- 0 0 0 4-. O O r- Table 3 o 56 Table 4 Ex.No R> RB R6 R' W Data u D- Table 5 SJ SJ z Z SJ J z O K X 2 T) NJ 9 * TJ o X Z SJ x z x ~ - z z s * X X X X X X X X X X I X X X X X X X X X X X X X X X X X " X X X X X X X X X X X I x x x x x x x x x x x x x x x x x x x x i X o o X X o o X X o o o o o o o o O O O O O O O tΛ ^ ^ o o o O O O O O tΛ Λ Λ o o t X SXJ SXJ SXJ SXJ NXJ NXJ NX o o o j NO ) O O o IJ to to t SJ SJ SJ SJ SJ tO tO NJ NJ NXJ NXJ NXJ NXJ NXJ NXJ tOO O O SXJ SXJ oo oo oo oo oo oo oo oo oo oo oo oo oo oo O O O O O O O O O O O O O O X X X X X X X X X X X X X X X I z z z z z z z z z z z z z z z N N ~ JU JU JU JU J JU JU JU JU zJU JU J— zU z z z z zJ NzJ NzJ NzJ NzJ zJ NzJ NzJ NJ NJ NzJ NzJ Ex.No R 6 R 7 R° > R9 R 10 ?χ Data CH 3 CH 3 So 3 & 2 NJ T| x z Tl o X _ Z__. Tl ό X £ z ON ON ON ON ON 00 00 00 00 00 VO oo z z z z 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Λ O O O O O O O O O O O O / 0 o vo oo — 1 ON LΛ 4-- LO J oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo O O O O O O O O CΛ CΛ O O O O O O O O O O O O CΛ CΛ o o o o o o o o o o o o o o o o o o o o o o o o o o o N 00 00 00 00 OO 00 00 ON ON LΛ LΛ 2 LO o 2 g 4-. oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo o o o o o o o X * X z X z X X z CΛ CΛ CΛ CΛ CΛ CΛ CΛ O O O O O VO vO vo vo VO vo vo vo vo vo 00 00 00 00 O O s 00 00 oo to — O vδ 00 -o LoΛ s 2 g 3° LO SJ ■— t Z £Z o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o O O O O O O z z X z X CΛ CΛ CΛ CΛ CΛ X zX z X z X z CΛ CΛ CΛ CΛ O O O O O Table 9 Ex No. R3 R 10 Daia CH 2 CH 2 Ph Table 10 H Ex No. R R 10 Daia 953 CH 3 CH 3 954 (H 3 C) 3 C CH 3 GG 955 CH 2 CH 2 Ph Table 11 R λ = H 2 N ExNo. R RB R 6 R 7 V w Daia KK 6 c ε ^ Table 12 65 R x = H,N ExNo. R RB R' W Data MM 9C SJ SJ SJ SJ NJ SJ SJ SJ SJ NJ NJ vO OO -O ON LΛ 4-. L tO ι— ' O VO LO NJ LO SJ LO SJ LO SJ LO to LO SJ LO NJ W NJ LO Z τι C O X J ; . " •" O- O O X - ; ■ ' . " 0- θ θ χ .; T.-J .- p. o o x τι -• X X z τι X X Z Z T1 T1 -A- . X Z Z Z. Z Tl LO LO J J LO LO Li LO LO X X X L.J LO LO LO kU M-, JU JU JU JU JU JU »--— «-U JU JU JU JU JU U to JU JU JU JU JU JU JU JU JU JU JU JU JU JU JU JU JU JU JU JU JU JU JU JU JU JU o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o LO LO LO LO tO NJ tO NJ NJ NJ NJ SJ Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z to LO SJ i iZ LO tO LO to Q O X ■ r O x TJ o X Z Z TJ o X X X X X LO LO LO J- _ d MM JU MM MM MM ^ MM JU MM JU JU <-9 0) tr LO ID JU JU JU JU JU JU JU JU JU JU JU JU JU MM JU MM MM M MM U U U JU ) O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O t to NJ to »-. μ_. ) _ k -. Q O O O O O O O O Q vo vo vo vp vo vp £ S oo 00 vo z z O (j X X TJ Tl X X fc z z Z Z Z Z O 0 x z z X O O X X X X < z z t »9 to NJ z z z t? vo l oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo O O O O O O O O CΛ CΛ CΛ CΛ CΛ CΛ CΛ CΛ CΛ CΛ CΛ CΛ O O O O O O O O O O O O CΛ CΛ O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O LO LO LO LO LO LO LO LO LO 4-. 4-. 4- 4-- OO ON LΛ g ON vo ns oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo C Λ C Λ C Λ CΛ CΛ C Λ CΛ O O O O O O O O O O O O O C Λ C Λ CΛ CΛ CΛ CΛ CΛ CΛ CΛ CΛ CΛ O O O O o o o o o o o o o o o o o o o o LO LO LO LO LO LO LO LO LO LO ON ON ON ON ON ON ON OS ON LΛ 4- OO -O O LΛ 4- LO t—o . vo vo Tl Tl O O O O oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo CΛ CΛ CΛ CΛ CΛ CΛ O O O O O O O O O O O O z z z 32 to to t t to to SJ to S o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o CΛ O O O O O O O O O O O O g g z X CΛ OO CΛ OO CO CΛ 00 Xz Xz Xz o o ou oυ oυ oυ oυ υo oυ oυ oυ oυ υo oυ ou oυ oυ oυ oυ oυ oυ oυ oυ ON If) 00 ON © m LO LΛ 8 4-. LO 4-. LO z z z z TJ (j (j X J sV X X Λ z z z z s? 8 J to tθ Nj Nj tθ tθ lθ t sj N> o NJ J N tO SJ SJ NJ SJ NJ SJ oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo CΛ CΛ CΛ CΛ CΛ C Λ CΛ O O O O O O O O O O O O O CΛ CΛ CΛ Λ CΛ CΛ CΛ CΛ CΛ CΛ CΛ O O O O o o o o o o o o o o o o o c o o o c o o o o o o o o o o o o o o o o o LΛ LΛ LΛ LΛ LΛ LΛ LΛ LΛ LΛ LΛ LΛ LΛ LΛ LΛ SJ t SJ to SJ Ov. LΛ 4-. -— O ON LΛ LO NJ <-4 OOO o-o o oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo oo z X z X CΛ CΛ CΛ CΛ CΛ CΛ CΛ CΛ CΛ CΛ CΛ CΛ O O O O O O O O O O O O U CΛ CΛ CΛ CΛ O O O O 1629 Table 16 R x = H 2 N, Z=C(=0) Ex No. .10 Data 1630 CH 3 CH 3 1631 (H 3 C) 3 C CH 3 Table 17 Ex No. R 11 R 10 Daia Table 18 Ex No. .11 .10 Da 1642 single bond CH 2 CH 2 Ph CO RR TABLE 19 ιoε Ex No. R3 -10 Data 1643 CH 2 Ph CH 2 CH 2 Ph CO NHCH 3 SS 1644 CH 2 Ph CH 2 CH 2 Ph CO H TT Table 20 Ex No. R3 R 10 R> Data 1645 CH 2 Ph CH 2 CH 2 Ph CO NHCH 3 UU 1646 CH 2 Ph CH CH 2 Ph CO H w DATA A HRMS Calcd for C 2 9H 42 BN 3 0 6 : 540.3241 Found 540.3248. B HRMS Calcd for C 30 H 4 4BN 3 O 6 : 554.3401 Found: 554.3404. C HRMS Calcd for C 31 H 47 BN 3 0 6 : 568.3558. Found 568.3558. D HRMS Calcd for C 29 H 42 BN 3 0 6 : 540.3245 Found: 540.3248. E HRMS Calcd for C 33 H 51 BN 3 0 6 : 596.3871. Found: 596.3870. F HRMS Calcd for C 3 3H 51 BN3θg: 596.3871. Found: 596.3857. G HRMS Calcd for C3 6 H 48 BN 3 0 6 : 630.3714. Found: 630.3709. H HRMS Calcd for C 30 H 44 BN 3 O 7 : 570.3351. Found: 570.3353. I LRMS Calcd for C 30 H 5 BN 3 θ8S : 618.3. Found: 618.4. J HRMS Calcd for C 31 H 46 BFN 3 0 6 : 586.3464. Found: 586.3456. K HRMS Calcd for C 30 H 46 BN 4 Og: 569.3510. Found: 569.3501. L HRMS Calcd for C 3e H 5 2BN 3 0g: 658.4027. Found: 658.4036. M HRMS Calcd for C28-H39BN3O5 (ethylene glycol ester) : 508.2983. Found: 508.2999. N HRMS Calcd for C27H39BN3O5 (ethylene glycol ester) : 522.3139. Found: 522.3123. 0 LRMS Calcd for C 2 gH3 BFN 3 θ5 (ethylene glycol ester) : 526. Found: 526. P HRMS Calcd for C 35 H 49 BN 3 0 4 S : 618.3537. Found: 618.3537. Q HRMS Calcd for C 3 gH 51 BN3θ 5 : 616.3922. Found: 616.3910. R HRMS Calcd for C3 7 H53BN3O5 : 630.4078. Found: 630.4060. S HRMS Calcd for C 35 H 50 BN 4 O 5 : 617.3874. Found: 617.3876. T LRMS Calcd for C 3 gH 50 BFN 3 O 5 : 634. Found: 634.5. U LRMS Calcd for C 3 gH 52 BN 4 0 5 : 631. Found: 631.3. V HRMS Calcd for C 3 7H 5 3BN 3 θ5 : 630.4078. Found: 630.4071. W HRMS Calcd for C3 6 H 48 BN 3 0g: 618.3714. Found: 618.3713. X HRMS Calcd for C 36 H 51 BN 3 0 6 : 632.3871. Found: 632.3857. Y LRMS Calcd for C 36 H 51 BN 4 0 : 615. Found: 615.5. Z HRMS Calcd for C 29 H 44 BN 4 0 5 : 526.3452. Found: 526.3460. AA HRMS Calcd for C 30 H 46 BN3θ 5 : 540.3609. Found: 540.3604. BB HRMS Calcd for C 30 H 47 B 3θ 5 : 540.3609. Found: 540.3620. CC HRMS Calcd for C 31 H 49 BN3θ 5 : 554.3765. Found: 554.3769. DD HRMS Calcd for C 33 H 5 3BN 4 0 7 : 582.4078. Found: 582.4071. EE HRMS Calcd for C 30 H 48 BN 4 O 5 : 555.3718. Found: 555.3735. FF HRMS Calcd for C 35 H 5 gBN 4 0 7 : 655.4242. Found: 655.4234. GG HRMS Calcd for C 26 H 47 BN 3 θ 5 : 492.3609. Found: 492.3600. HH HRMS Calcd for C 3 3H 47 BN 3 θ 5 : 576.3609. Found: 576.3593. II HRMS Calcd for C33H 53 BN3O 5 : 582.4078. Found: 582.4092. JJ HRMS Calcd for C 40 H 53 B 3 O 5 : 666.4078. Found: 666.4089. KK LRMS Calcd for C 2 gH 3 gBFN 5 0 5 : 528.3. Found: 528.3. LL HRMS Calcd for C 36 H 51 BN 5 0 5 : 644.3983. Found: 644.3977. MM LRMS Calcd for C 3 gH 50 BFN 5 O 5 : 662. Found: 662. NN HRMS Calcd for C 28 H 42 BN 4 0 6 S: 573.2918. Found: 573.2919. OO HRMS Calcd for C 32 H 50 BN 4 OgS : 629.3544. Found: 629.3524. PP HRMS Calcd for C 29 H 42 BN 3 0 5 S : 571.3126. Found: 571.3138. QQ HRMS Calcd for C 35 H 48 BN 4 0 6 S : 663.3388. Found: 663.3374. Ill RR HRMS Calcd for C 29 H 43 BN 3 0 5 : 524.3300. Found: 524.3305. SS LRMS Calcd for C37H 53 BN 5 O 5 : 653. Found: 658 TT LRMS Calcd for C3 6 H 50 BN 4 O 5 : 629. Found: 629 UU LRMS Calcd for C 27 H 39 BN 5 O 5 : 524. Found: 524 W LRMS Calcd for C 26 H 3 6BN 4 O 5 : 495. Found: 495 WW HRMS Calcd for C 35 H 48 BFN 3 θ 6 : 636.3620. Found: 636.3612. Utility The compounds of formula (I) are useful as inhibitors of serine proteases and notably human thrombin, plasma allikrein and plas in . Because of their inhibitory action, these compounds are indicated for use in the prevention or treatment of physiological reactions, blood coagulation and inflammation, catalyzed by the aforesaid class of enzymes . Inhibition constants .were determined by the method described by Kettner et al . in J. Bi ol . Chem . 265, 18289-18297 (1990), herein incorporated by reference. In these assays, thrombin-mediated hydrolysis cf the chromogenic substrate S2238 (Helena Laboratories, Beaumont, TX)- was monitored spectrophotometrically . Addition of an inhibitor to the assay mixture results n decreased absorbance and is indicative of thrombin inhibition. Human thrombin (Enzyme Research Laboratories, Inc., South Bend, IN) at a concentration of 0.2 nM in 0.10 M sodium phosphate buffer, pH 7.5, 0.20 M NaCl, and 0.5% polyethylene glycol 6000, was incubated with various substrate concentrations ranging from 0.20 to 0.02 mM. After 25 to 30 minutes of incubation, thrombin activity was assayed by monitoring the rate of increase in absorbance at 405 nm which arises owing to substrate hydrolysis. Inhibition constants were derived from reciprocal plots of the reaction velocity as a function of substrate concentration using the standard method of Lineweaver and Bur . Using the methodology described above, representative compounds of this invention were evaluated and found to exhibit a K± of less than 1 mM, thereby confirming the utility of the compounds of the invention as effective thrombin inhibitors. The ability of the compounds to inhibit coagulation was assayed in normal rabbit plasma which was prepared by diluting blood 1:10 with 3.2% aqueous citric acid followed by centrifugation . Bovine thrombin was obtained from Sigma and diluted to 24 NIH units/mL. Plasma ( 0.2 mL) and buffer (0.05 mL, 0.10 M Tris [hydroxymethyl]-aminomethane hydrochloride, pH 7.4, 0.9% (w/v) sodium chloride, and 2.5 mg/mL bovine serum albumin) containing inhibitor were incubated 3 min at 37 °C in a fibrameter. Reactions were initiated by adding thrombin (0.05 mL) to achieve a final concentration of 4 NIH units/mL. The effectiveness of compounds as anticoagulants is reported as the level of inhibitor required to prolong clotting to that observed for 2 NIH units/mL of .thrombin in the absence of inhibitor. In this assay then, better inhibitors require lower concentrations to delay clot formation. Representative compounds of this invention were evaluated and found to be active. Since the compounds of formula (I) have anti- thrombogenic properties, they may be employed when an anti-thrombogenic agent is indicated, such as for the control of the coagulation of the fibrinolysis system in mammals or they may be added to blood for the purpose of preventing coagulation of the blood due to contact with blood collecting or distribution containers, tubing or apparatus. Generally, these compounds may be administered orally, parenterally or intravenously to a host to obtain an anti-thrombogenic effect. The dosage of the active compound depends on the mammalian species, body weight, age, and mode of administration as determined by one skilled in the art. In the case of large mammals such as humans, the compounds may be administered alone or in combination with pharmaceutical carriers or diluents at a dose of from 0.02 to 15 mg/kg to obtain the anti-thrombogenic effect, and may be given as a single dose or in divided doses or as a sustained release formulation. Pharmaceutical carriers or diluents are well known and include sugars, starches and water, which may be used tc make tablets, capsules, injectable solutions or the like which can serve as suitable dosage forms for administration of the compounds of this invention. Remington's Pharmaceutical Sciences. A. Osol, is a standard reference text which discloses suitable pharmaceutical carriers and dosage forms. The disclosure of this text is hereby incorporated by reference for a more complete teaching of suitable dosage forms "for administration of the compounds of this invention .

Claims: WHAT IS CLAIMED IS A compound of formula ( i ; (I) or a pharmaceutically acceptable salt or prodrug thereof, wherein: a) - (C1-C12 alkyl)-X, or b) - (C2-C12 alkenyl)-X, or c) X is a) halogen, b) -CN, c) -N0 2 , d) -CF 3 , e) -S(0) p R 2 , f> -NHR 2 , g) -NHS(0) p R 2 , h) -NHC(=NH)H, i) -NHC (=NH) NHOH, j) -NHC(=NH)NHCN, k) -NHC(=NH)NHR 2 , 1) -NHC(=NH)NHC(=0)R 2 , m) -C(=NH)H, n) -C(=NH)NHR 2 , O) -C(=NH)NHC(=0)R 2 , p) -C(=0)NHR 2 , q) -C(=0)NHC(=0)R 2 , r) -C(=0)OR 2 , s) -OR 2 , t) -OC(=0)R 2 , u) -OC(=0)OR 2 , v) -OC(=0)NHR 2 , w) -OC(=0)NHC (=0)R 2 , x) -SC (=NH)NHR 2 ; R 2 is a) hydrogen, b) -CF 3 c) Cι-C alkyl, d) -(CH 2 ) q -aryl; R 3 and R 10 are independently selected at each occurrence from the group consisting of: a) hydrogen, b) halogen, c) - (CR 6 R 7 ) t W(CR 8 R 9 ) u -R 9 , d) - (CR 6 R 7 ) t W(CR 8 R 9 ) u -aryl, e) - (CR 6 R 7 ) t W(CR 8 R 9 ) u -heteroaryl, f ) - (CR 6 R ) t W(CR 8 R 9 ) u -heterocycle, g) - (CR 6 R 7 ) t W(CR 8 R 9 ) u -adamantyl, ) - (CR 6 R 7 ) t W(CR 8 R 9 ) u (C 5 -C 7 )cycloalkyl, i) 11! heteroaryl k) m) n) o) R e p ) r) nc R 3 and R 10 when taken together form a ring such as : a) - (CR 6 R 7 ) t (CR 8 R 9 ) U -W- (CR 8 R 9 ) u (CR 6 R 7 ) t ; b) -<CR 6 R 7 ) t W(CR 8 R 9 ) u -aryl-(CR 8 R 9 ) u W(CR 6 R 7 ) t -; c) - (CR 6 R 7 ) t W(CR 8 R 9 ) u -heteroaryl- (CR 8 R 9 ) U W(CR 6 R 7 ) t -; d) -(CR 6 R 7 ) t W(CR 8 R 9 ) u -heterocycle-(CR 8 R 9 ) u W(CR 6 R ) t -; e) - (CR 6 R 7 ) t W(CR 8 R 9 ) u -W-(CR 8 R 9 ) u W(CR 6 R 7 ) t -; R 4 and R 5 are independently selected at each occurrence from the group consisting of: a) hydrogen, b) C 1 -C 4 alkyl, c) C 1 -C 4 alkoxy, d) C 5 -C 7 cycloalkyl, e) phenyl, f) benzyl; R 6 , R 7 , R 8 and R 9 are independently selected at each occurrence from the group consisting of: a) hydrogen, b) Ci-Cβ alkyl, c) C 1 -C 6 alkoxy, d) C3-C8 cycloalkyl, e) ' aryl, f) heterocycle, g) heteroaryl, h) -W-aryl, i) -(CH 2 ) w C(=0)OR 4 , j) R 6 or R 7 can ' alternatively be taken together with R 6 or R 7 on an adjacent carbon atom to form a direct bond, thereby to form a double or triple bond between said carbons, or k) R 8 or R 9 can alternatively be taken together with R 8 or R 9 on an adjacent carbon atom to form a direct bond, thereby to form a double or triple bond between said carbons; R 11 is a) hydrogen, b) C1-C4 alkyl, c) C1-C4 thioalkyl, d) -(CR 6 R 7 ) t W(CR 8 R 9 ) u -aryl, e) -(CR 6 R 7 ) t W(CR 8 R 9 ) u -heteroaryl, f) -(CR 6 R 7 ) t W(CR 8 R 9 ) u -heterocycle, or g) - (CR 6 R 7 ) t W(CR 8 R 9 ) u -R 9 ; R 11 and V, when taken together, can also be: a) keto, b) =NR 10 , c) =C[ (CR 6 R 7 ) t W(CR 8 R ) u R 2 ] 2 , or d) - (CR 6 R 7 ) t W(CR 8 R 9 ) u -W-(CR 6 R 7 ) t W(CR 8 R 9 ) u - A is a) -BY 1 Y 2 , b) -C(=0)CF 3 , c) -C(=0)CF 2 CF 3 , d) -PO3H2 d) -C(=0)H, e) -C (=0) -1-piperdinyl, f) -C(=0)CH 2 OCH 2 CF 3 , g) CH 2 C1 h) S0 2 F; Y 1 and Y 2 are a) -OH, b) -F, c) -NR 4 R 5 -, d) -Ci-Cβ alkoxy, or; when taken together Y 1 and Y 2 form: e) a cyclic boron ester where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be N, S, or 0, f) a cyclic boron amide where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be N, S, or 0, g) a cyclic boron amide-ester where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be N, S, or 0; W can be independently selected at each occurence from the group consisting of: a) -(CH 2 ) X -, b) -C(=0)-, c) -C(=0)0-, d) -C(=0)NR 4 -, e) -0-, f) -0C(=0)-, g) -0C(=0)0-, h). -0C(=0)NR 4 -, i) -NR 4 -, j) -NR 4 C(=0)-, k) -NR 4 C(=0)0-, 1) -NR C(=0)NR 5 -, m) -NR S(0) p - n) -S(0) p -, o) -S(0) p 0-, p) -S(0) p NR 4 -, q) -S(0) p NR 4 C(=0)-, r) -S(0) p NR C(=0)NR 5 -; V is selected from the group consisting of: a) -(CH 2 ) X -, 12: b) -(CH 2 ) x C(=0)-, c) -(CH 2 ) x C(=0)0-, d) -C(=0) (CH 2 ) X -, e) -0-(CH 2 ) x -, f) -0(CH 2 ) x C(=0)-, g) -0(CH 2 ) x C(=0)0-, h) -0(CH 2 ) x C(=0)NR 4 -, i) -0(CH 2 ) x S(0) p -, j) -(CH 2 ) x S(0) p -, k) -(CH 2 ) x S(0) p O-, 1) -(CH 2 ) x S(0) p NR 4 -, m) -(CH 2 ) x S(0) p NR C(=0)-, n) -(CH 2 ) x S(0) p NR 4 C(=0)NR 5 - ] o) -(CH 2 ) X NR 4 -, p) -(CH 2 ) x NR 4 C(=0)-, q) -(CH 2 ) x NR 4 C(=0)0-, r) - (CH 2 ) X NR 4 C (=0)NR 5 -, s) -(CH 2 ) x NR 4 S(0) p -; . Z is selected from the group consisiting of a) - (CH 2 ) y _- , b) -(CH 2 ) x C(=0)-, c) -C(=0) (CH 2 ) X -, d) - (CH 2 ) x C(=0)0-, e) - (CH 2 ) x C(=0)NR 4 -, f) - (CK 2 ) X R 4 -, g) - (CH 2 ) x NR 4 C(=0)-, h) - (CH 2 ) χ NR 4 C(=0)0-, i) - (CH 2 ) X NR 4 C(=0)NR5-, j) -(CH 2 ) χ NR 4 S(0) p -, k) -(CH 2 ) x S(0) p -, 1) -(CH 2 ) x S(0) p NR 4 -, m can be 0 to 4; n can be 0 to 4; p can be 0 to 2 q can be 0 to 4; r, s, t, u, and v are independently selected at each occurrence from 0 to 6, w and x are independently selected at each occurence from 0 to 4; with the following provisos: (a) when V is (CH 2 ) >: , x cannot be 0 when R 3 is hydrogen; (b) when Z is - (CH 2 ) X C (=0) - and -C (=0) (CH 2 ) X and x is C, R 10 cannot be halogen; wherein aryl is defined as phenyl, fluorenyl, biphenyl and naphthyl, which may be unsubstituted or include optional substitution with one to three substituents; heteroaryl is 2-, or 3-, or 4-pyridyi; 2-or 3-furyi; 2- cr 3-benzofuranyl; 2-, or 3-thiophenyl; 2- or 3- benzo [b]thiophenyl; 2-, or 3-, or 4-quinolinyl; 1-, or 3-, or 4-isoquinolinyl; 2- or 3-pyrrolyl; 1- or 2- or 3- indolyl; 2-, or 4-, or 5-oxazolyl; 2-benzoxazolyl ; 2- or 4- or 5-imidazolyl; 1- or 2- benzimidazolyl; 2- or 4- or 5-thiazolyl; 2-benzothiazolyl; 3- or 4- or 5- isoxazolyl; 3- or 4- or 5-pyrazolyl; 3- or 4- or 5- isothiazolyl; 3- or 4-pyridazinyl; 2- or 4- or 5- pyrimidinyl; 2-pyrazinyl; 2-triazinyl; 3- or 4- cinnolinyl; 1-phthalazinyl; 2- or 4-quinazolinyl; or 2- quinoxalinyl ring; said ring(s) may be unsubstitued or 12: include optional substitution with one to three substituents; heterocycle is 2- or 3-pyrrolidinyl, a 2-, 3-, or 4- piperidinyl, or a 1-, 3-, or 4-tetrahdroisoquinolinyl, 1-, 2-, or 4-tetrahydroquinoiinyl, 2- or 3- tetrahydrofuranyl, 2- or 3-tetrahydrothioρhene, 1-, 2-, 3-, or 4-piperazinyl, and 1-, 2-, 3-, or 4-morpholino; said ring(s) which may be unsubstituted or include optional substitution with one to three substituents; cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl and cyclooctyl; the substituents which may be attached to the ring(s) above may be independently selected at each occurrence from the group selected from: halogen,-CF 3 , Cι~C 4 alkyl,nitro, phenyl, -(CH 2 ) r R 4 , -(CH 2 r C(=0) (CH 2 ) S R 4 , -(CH 2 ) r C(=0)0(CH 2 ) s R 4 , -(CH 2 r C (=0) N [ (CH 2 ) S R 4 ] [ (CH 2 ) S R 5 ] , methylenedioxy, Cι~C alkoxy, -CH 2 ) r 0(CH 2 ) S R 4 , - (CH 2 ) r OC (=0) (CH 2 ) S R 4 -(CH 2 r 0C(=0)0(CH 2 ) s R 4 , -(CH 2 r 0C(=0)N[ (CH 2 ) S R J [ (CH 2 ) S R5] , -(CH 2 r 0C(=0)N[ (CH 2 ) S R 4 ] [C(=0) (CH 2 ) S R5] , -(CH 2 0) p (CH 2 ) S R 4 , - (CH 2 ) r S (0) p (CH 2 ) S C (=0) R 4 , -(CK 2 0) p (CH 2 ) s C(=0)0R 4 , -(CH 2 0) p N[ (CH 2 ) S R 4 ] [ (CH 2 ) S R 5 J , -(CH 2 0) p N[ (CH 2 ) S R 4 J [C(=0) (CH 2 ) S R5] , -(CH 2 (CH 2 ) S R 4 ] [ (CH 2 ) S R5], -(CH 2 - N (CH 2 ) S R 4 ] [C(=0) (CH 2 ) S R5], -(CH 2 r N (CH 2 ) S R 4 ] [C(=0)0(CH 2 ) S R5], -(CH 2 ,N (CH 2 ) s R 4 ]CON[ (CH 2 ) S R 4 ] [ (CH 2 ) S R5] . -(CH 2 rN (CH 2 ) s R 4 ]C(=0)-N[ (CH 2 ) S R 4 J [C (=0) (CH 2 ) S R 5 ] -(CH 2 ^ N (CH 2 ) S R 4 ] [S(0) p (CH 2 ) s R5] . 2. A compound of claim 1 wherein: R 1 is (C 3 -C 4 alkyl) ; 5 X is selected from the group consisting of: -NHC(=NH)H, -NHC(=NH)NHR 2 , -NH 2 or -SC (=NH)NHR 2 ; R 2 is hydrogen or Cχ-C 4 alkyl. 0 3 . A compound of claim 2 having formula ( Ia ) wherein : 5 ( Ia ) or a pharmaceutically acceptable salt or prodrug thereof, wherein: C R 1 is (C3-C 3 alkyl) ; X is selected from the group consisting of: -NHC(=NH)H, -NHC(=NH)NHR 2 , -NH 2 or -SC (=NH)NHR 2 ; 5 R 2 is hydrogen or C 1 -C 4 alkyl ; R 3 and R 10 are independently selected at each occurrence from the group consisting of: a) hydrogen, 0 b) halogen, c) - (CR 6 R 7 ) t W(CR 8 R 9 ) u -R 9 d) -(CR 6 R ) t W(CR 8 R 9 ) u -aryl e) - (CR 6 R 7 ) t W(CR 8 R 9 ) u -heteroaryl; R 4 and R 5 are independently selected at each occurrence from the group consisting of: a) hydrogen, b) C1-C4 alkyl, c) C1-C4 alkoxy, d) phenyl, or e) benzyl; R 6 , R 7 , R 8 , R 9 are independently selected at each occurrence from the group consisting of: a) hydrogen b) Ci-Cg alkyl, c) aryl, d) -(CH 2 ) w C(=0)OR 4 , or; Y 1 and Y 2 are a) -OH, b) -F, c) -NR R 5 -, d) -Ci-Cβ alkoxy, or; when taken together Y 1 and Y 2 form: e) a cyclic boron ester where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be N, S, or 0, f) a cyclic boron amide where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be N, S, or 0, g) a cyclic boron amide-ester where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be N, S, or O; W can be independently selected at each occurrence from 5 the group consisting of: a) -(CH 2 ) X -, b) -0-, c) -S(0) p -, d) -NR 4 -, 10 e) -NR 4 C(=0)-, f) -NR 4 C(=0)0-, V is selected from the group consisting of: a) -(CH 2 ) X -, 15 b) -0(CH 2 ) x -, c) -0(CH 2 ) x (C=0)-, d) -(CH 2 ) X S(0) P -, e) -(CH 2 ) X NR 4 - f) - (CH 2 ) x NR 4 C(=0)-, 20 g) - (CH 2 ) x NR 4 C(=0)0-; Z is selected from the group consisiting of: a) -(CH. 2 ) X C(=0)-, b) -C(=0) (CH 2 ) X -, 25 c) -(CH 2 ) x C(=0)0-, p can be 0 or 2; r can be independently selected at each occurrence from 30 0 to 3; ) s can be independently selected at each occurrence from 0 to 3; 35 t can be independently selected at each occurrence from 0 to 2; u can be independently selected at each occurrence from 0 to 2; w can be independently selected at each occurrence from 0 to 2; x can be independently selected at each occurrence from 0 to 3; with the following provisos: (a) when V is (CH 2 ) X , x can not be 0 when R 3 is hydrogen; (b) when Z is - (CH 2 ) X C (=0) - and -C (=0) (CH 2 ) X and x is 0, R 10 can not be halogen; wherein aryl is phenyl, fluorenyl, biphenyl and naphthyl, which may be unsubstituted or include optional substitution with one to three substituents; heteroaryl is 2-, 3-, or 4-pyridyl; 2-, or 3-furyi; 2-, or 3-thiophenyl; 2-, 3-, or 4-quinolinyl; or 1-, 3-, or 4-isoquinolinyl, which may be unsubstitued or include optional substitution with one to three substituents; heterocycle is 1-, 3-, or 4-tetrahdroisoquinolinyl, 2- or 3-pyrrolidinyl, and 2-, 3- or 4-piperidinyl, which may be unsubstituted or include optional substitution with one to three substituents; cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl and cyclooctyl; 126 the substituents which may be attached to the aryl, heteroaryl and heterocycle ring(s) may be independently selected at each occurrence from the group selected from: halogen,-CF 3 , C 1 -C 4 alkyl,nitro, phenyl, -(CH 2 ) r R 4 , "(CH 2 r C(=0) (CH 2 ) S R 4 , -(CH 2 ) r C(=0)0(CH 2 ) s R 4 , ~(CH 2 r C(=0)N[ (CH 2 ) S R 4 ] [ (CH 2 ) S R5], methylenedioxy, C 1 -C 4 alkoxy, -CH 2 ) r O (CH 2 ) S R 4 , - (CH 2 ) r OC (=0) (CH 2 ) S R 4 , "(CH 2 r OC(=0)0(CH 2 ) s R 4 , 0 -(CH 2 r 0C(=0)N[ (CH 2 ) s R 4 ] [ (CH 2 ) S R 5 ], "(CH 2 r OC(=0)N[ (CH 2 ) s R 4 ] [C(=0) (CH 2 ) S R 5 ], -(CH 2 r S (0) p (CH 2 ) S R 4 , - (CH 2 ) r S (0) p (CH 2 ) S C (=0) R 4 , "(CH 2 r S(0) p (CH 2 ) s C(=0)OR 4 , -(CH 2 r S(0) p N[ (CH 2 ) S R 4 ] [ (CH 2 ) S R5], _ <- -(CH 2 r S(0) p N[ (CH 2 ) S R 4 ] [C(=0) (CH 2 ) S R5] . "(CH 2 N[ (CH 2 ) S R 4 ] [ (CH 2 ) S R 5 J, ~(CH 2 N[ (CH 2 ) S R 4 ] [C(=0) (CH 2 ) S R5], -(CH 2 N[ (CH 2 ) S R 4 ] [C(=0)0(CH 2 ) S R5], -(CH 2 r N[ (CH 2 ) s R ]CON[ (CH 2 ) S R 4 ] [ (CH 2 ) S R 5 ] , 0 ~(CH 2 r N[ (CH 2 ) s R 4 ]C(=0)-N[ (CH 2 ) S R 4 ] [C(=0) (CH 2 ) S R5] , -(CH 2 r N[ (CH 2 ) S R 4 ] [S(0) p (CH 2 ) s R 5 ] . 4. A compound of claim 3 wherein: 5 R 3 is independently selected from the group consisting of: benzyl, phenyl, phenethyl, (3-phenyl)prop-1-yl, (2- methy1-1-phenyl)prop-2-yl, (2-methyl-2-phenyl)prop- 0 1-yl, 1, 1-diphenylmethyl, phenoxymethyl, phenylsulfonylmethyl, 2- (m-fluorophenyl) ethyl, , 2- (3-pyridyl) ethyl, (m-aminophenyl)methyl, (m- methylphenyl)methyl, (p-methylphenyl)methyl, 1- naphthylmethyl; 5 R 10 is independently selected from the group consisting of: methyl, t-butoxy, benzyloxy, phenethyl, benzyl, phenoxymethyl, isopropyl, isoamyl, N-methyl-N-t- butoxycarbonylaminomethyl, N-methylaminomethyl, ( - methyl)phenethyl, (m-fluoro) phenethyl, (m- methyl)phenoxymethyl, (3-pyridyl) ethyl; R 11 is hydr gen; V is independently selected from the group consisting of: 0, -OC(=0)-, S, -ΝH-; Z is -C(=0)- 5. A compound of claim 4 of the formula (lb) selected from the group consisting of: (lb) selected from the list consisting of the compound of formula (lb) wherein R 3 is phenyl and R 10 is methyl; the compound of formula (lb) wherein R 3 is phenylmethyl and R 10 is methyl; the compound of formula (lb) wherein R 3 is phenethyl and R 10 is methyl; the compound of formula (lb) wherein R 3 is 3- phenylprop-1-yl and R 10 is methyl; the compound of formula (lb) wherein R 3 is 1,1- dimethyl-2-phenylethyl and R 10 is methyl; the compound of formula (lb) wherein R 3 is 2,2- dimethyl-2-phenylethyl and R 10 is methyl; the compound of formula (lb) wherein R 3 is diphenylmethyl and R 10 is methyl; the compound of formula (lb) wherein R 3 is phenoxymethyl and R 10 is methyl; the compound of formula (lb) wherein R 3 is phenylsulfonylmethyl and R 10 is methyl; the compound of formula (lb) wherein R 3 is (m- fluorophenyl) ethyl and R 10 is methyl; the compound of formula (lb) wherein R 3 is (3- pyridyl) ethyl and R 10 is methyl; the compound of formula (lb) wherein R 3 is phenylethyl and R 10 is phenethyl. 6. A compound of claim 4 of the formula (Ic) selected from the group consisting of: (Ic) selected from the list consisting of: the compound of formula (Ic) wherein V is sulfur, R 3 is phenyl and R 10 is phenethyl; the compound of formula (Ic) wherein V is oxygen, R 3 is phenylmethyl and R 10 is phenethyl; the compound of formula (Ic) wherein V is oxygen, R 3 is phenylmethyl and R 10 is 3-phenylpropyl; the compound of formula (Ic) wherein V is oxygen, R 3 is phenylmethyl and R 10 is (m- methyl)phenoxymethyl; the compound of formula (Ic) wherein V is oxygen, R 3 is phenylmethyl and R 10 is ( - fluoro)phenoxymethyl; the compound of formula (Ic) wherein V is oxygen, R 3 is phenylmethyl and R 10 is {m- methylphenyl)ethyl; the compound of formula (Ic) wherein V is oxygen, R 3 is phenylmethyl and R 10 is (m- fluorophenyl) ethyl; the compound of formula (Ic) wherein V is oxygen, R 3 is phenylmethyl and R 10 is phenoxymethyl; the compound of formula (Ic) wherein V is oxygen, R 3 is (m-fluorophenyl)methyl and R 10 is phenethyl; the compound of formula (Ic) wherein V is amino, R 3 is phenylmethyl and R 10 is phenethyl; the compound of formula (Ic) wherein V is oxygen, R 3 is phenylmethyl and R 10 is methyl; the compound of formula (Ic) wherein V is oxygen, R 3 is phenylmethyl and R 10 is 2-propyl; the compound of formula (Ic) wherein V is oxygen, R 3 is phenylmethyl and R 10 is isoamyl; the compound of formula (Ic) wherein V is oxygen, R 3 is (m-rnethylphenyl)methyl and R 10 is methyl; the compound of formula (Ic) wherein V is oxygen, R 3 is (p-methylphenyl)methyl and R 10 is methyl; the compound of formula (Ic) wherein V is oxygen, R 3 is (1-naphthyl)methyl and R 10 is methyl; the compound of formula (Ic) wherein V is oxygen, R 3 is phenylmethyl and R 10 is N-methyl -N-t- butoxycarbonylaminomethyl; the compound of formula (Ic) wherein V is oxygen, R 3 is phenylmethyl and R 10 is N-methylaminomethyl . 7. A compound of claim 4 of the formula (Id) selected from the group consisting of: ( I C ) selected from the list consisting of: the compound of formula (Id,) wherein V is oxygen, R 3 is phenylmethyl and R 10 is phenethyl; the compound of formula (Id) wherein V is oxygen, R 3 is (mrfluorophenyl)methyl and R 10 is phenethyl. the compound of formula (Id) wherein V is oxygen, R 3 is phenylmethyl and R 10 is (/n-methyl)phenethyl; 8. A pharmaceutical composition comprising a pharmaceutically suitable carrier and a therapeutically effective amount of a compound of claim 1. 9. A pharmaceutical composition comprising a pharmaceutically suitable carrier and a therapeutically effective amount of a compound of claim 2. 10. A pharmaceutical composition comprising a pharmaceutically suitable carrier and a therapeutically effective amount of a compound of claim 3. 11. A pharmaceutical composition comprising a pharmaceutically suitable carrier and a therapeutically effective amount of a compound of claim . 12. A pharmaceutical composition comprising a pharmaceutically suitable carrier and a therapeutically effective amount of a compound of claim 5. 13. A pharmaceutical composition comprising a pharmaceutically suitable carrier and a therapeutically effective amount of a compound of claim 6. 14. A pharmaceutical composition comprising a pharmaceutically suitable carrier and a therapeutically effective amount of a compound of claim 7. 15. A method of treating a physiological disorder in a warm blooded animal catalyzed by serine protease enzymes comprising administering to an animal in need of such treatment an effective amount of a compound of claim 1. 16. A method of treating a physiological disorder in a warm blooded animal catalyzed by serine protease enzymes comprising administering to an animal in need of such treatment an effective amount of a compound of claim 2. 17. A method of treating a physiological disorder in a warm blooded animal catalyzed by serine protease enzymes comprising administering to an animal in need of such treatment an effective amount of a compound of claim 3. 18. A method of treating a physiological disorder in a warm blooded animal catalyzed by serine protease enzymes comprising administering to an animal in need of such treatment an effective amount of a compound of claim . 19. A method of treating a physiological disorder in a warm blooded animal catalyzed by serine protease enzymes comprising administering to an animal in need of such treatment an effective amount of a compound of claim 5. 20. A method of treating a physiological disorder in a warm blooded animal catalyzed by serine protease enzymes comprising administering to an animal in need of such treatment an effective amount of a compound of claim 6. 21. A method of treating a physiological disorder in a warm blooded animal catalyzed by serine protease enzymes comprising administering to an animal in need of such treatment an effective amount of a compound of claim 7.

Inventors: PACOFSKY GREGORY JAMES, PRUITT JAMES RUSSELL, WEBER PATRICIA CAROL, PACOFSKY, GREGORY, JAMES, PRUITT, JAMES, RUSSELL, WEBER, PATRICIA, CAROL
Applicants: DU PONT MERCK PHARMA, THE DU PONT MERCK PHARMACEUTICAL COMPANY
Application year: 1994
Main classification: C07F5
IPC codes: A61K38, C07D207, C07F5, C07F9, C07K5